Quinoline and isoquinoline derivatives, a process for their production and their use as inflammation inhibitors

ABSTRACT

The invention relates to quinoline and isoquinoline derivatives of general formula I 
                 
 
a process for their production and their use as inflammation inhibitors.

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/369,583 filed Apr. 4, 2002.

The invention relates to quinoline and isoquinoline derivatives, aprocess for their production and their use as inflammation inhibitors.

From the prior art of DE 100 38 639 and WO02/10143, inflammationinhibitors of the general formula

are known, whereby the Ar radical comprises phthalides, thiophthalides,benzoxazinones or phthalazinones. In the experiment, these compoundsshow dissociations of actions between anti-inflammatory actions andundesirable metabolic actions and are superior to the previouslydescribed, nonsteroidal glucocorticoids or have at least just as good anaction.

The selectivity of the compounds of the prior art relative to the othersteroid receptors, however, still requires improvement.

The object of this invention was therefore to make available compoundswhose selectivity is improved relative to the other steroid receptors.

This object is achieved by the compounds according to the claims.

This invention therefore relates to compounds of general formula I

in which

-   A stands for an aryl group, a benzyl group or a phenethyl group,    whereby the aryl, benzyl or phenethyl group optionally can be    substituted by one or more radicals from the group C₁-C₅-alkyl,    C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-perfluoroalkyl, halogen,    hydroxy, cyano, nitro, —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—,    —O—CH═CH—, or —(CH₂)_(n+2)—, whereby n=1 or 2, and the terminal    oxygen atoms and/or carbon atoms are linked with directly adjacent    ring-carbon atoms, or NR⁴R⁵,    -   whereby R⁴ and R⁵, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,-   R¹ and R², independently of one another, mean a hydrogen atom, a    methyl or ethyl group or together with the carbon atom the chain of    a C₃-C₆-cycloalkyl ring,-   R³ means a C₁-C₃-alkyl group or a C₁-C₃-alkyl group that is    optionally partially or completely fluorinated,-   B means a methylene group that is optionally substituted by a methyl    or ethyl group, or a carbonyl group, and-   Q means a quinolinyl group or isoquinolinyl group that is linked via    any position and that optionally can be substituted by one or more    radicals from the group C₁-C₅-alkyl, which optionally can be    substituted by 1-3 hydroxy groups and/or 1-3 COOR⁶ groups,    C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-perfluoroalkyl, halogen,    hydroxy, a carbonyl-oxygen atom, cyano, nitro or NR⁴R⁵,    -   whereby R⁴ and R⁵, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,    -   COOR⁶, whereby R⁶ means hydrogen or a C₁-C₅-alkyl group,    -   (CO)NR⁷R⁸, whereby R⁷ and R⁸, independently of one another, mean        hydrogen or a C₁-C₅-alkyl group,    -   or a (C₁-C₅-alkylene)-O—(CO)—(C₁-C₅)alkyl group,        as well as their racemates or separately present stereoisomers        and optionally their physiologically compatible salts.

As group A, the aryl group is preferred.

The aryl group comprises phenyl and naphthyl. Phenyl is preferred.

On the ring, the substituted aryl, benzyl or phenethyl groups carry 1-3substituents, preferably 2 substituents, in addition to the linkage withthe chain.

The following substitution patterns on ring A are a special subject ofthe invention: 2,5-disubstituted phenyl derivatives and2,4-disubstituted phenyl derivatives, whereby the 1-position is occupiedby the linkage to the chain.

Special subjects of the invention are compounds that on the aryl radicalcarry one or more substituents that are selected from the groupC₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-perfluoroalkyl, halogen, hydroxy,nitro, —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, and —(CH₂)_(n+2)—,whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms arelinked to directly adjacent ring-carbon atoms.

Quite especially preferred are compounds of formula I, in which A meansa phenyl ring that is substituted by a hydroxy or methoxy group and ahalogen group, in addition to the linkage with the chain.

The C₁-C₅-alkyl groups in A, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ can bestraight-chain or branched and can stand for a methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl or n-pentyl,2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl orethyl group is preferred. They can optionally be substituted by 1-3hydroxy groups and/or 1-3 COOR⁶ groups. Hydroxy groups are preferred.

A (C₁-C₅-alkylene)-O—(CO)—(C₁-C₅)alkyl group is defined as, for example,a —CH₂—O—CO—CH₃ group.

For a partially or completely fluorinated C₁-C₃-alkyl group, thefollowing partially or completely fluorinated groups are suitable:fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl,tetrafluoroethyl, and pentafluoroethyl. Of the latter, thetrifluoromethyl group or the pentafluoroethyl group is preferred.

Alkyl radicals R¹ and R² together with the carbon atom of the chain canform a 3- to 6-membered ring. The cyclopropyl ring is preferred.

The C₁-C₅-alkoxy groups in A and Q can be straight-chain or branched andstand for a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,iso-butoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy,2-methylbutoxy or 3-methylbutoxy group. A methoxy or ethoxy group ispreferred.

The C₁-C₅-alkylthio groups in A and Q can be straight-chain or branchedand stand for a methylthio, ethylthio, n-propylthio, iso-propylthio,n-butylthio, iso-butylthio, tert-butylthio or n-pentylthio,2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. Amethylthio group or an ethylthio group is preferred.

The designation halogen atom or halogen means a fluorine, chlorine,bromine or iodine atom. A fluorine, chlorine or bromine atom ispreferred.

The NR⁴R⁵ group can mean, for example, NH₂, N(H)CH₃, N(CH₃)₂,N(H)(CO)CH₃, N(CH₃)(CO)CH₃, N[(CO)CH₃]₂, N(H)CO₂CH₃, N(CH₃)CO₂CH₃, orN(CO₂CH₃)₂.

As alkyl radicals R⁴ and R⁵, C₁-C₃-alkyl is preferred.

As acyl radicals R⁴ and R⁵, (CO)—C₁-C₃-alkyl is preferred.

For the NR⁷R⁸ group, for example, NH₂, N(H)CH₃, N(CH₃)₂, N(C₂H₅)₂,NH(C₂H₅), N(C₃H₇)₂, N(C₄H₉)₂, and N(C₅H₁₁)₂ are suitable.

For radical B, the unsubstituted methylene group and the carbonyl groupare preferred. The methylene group is especially preferred.

Radical Q can be linked via any ring-carbon atom with the (NH) group ofthe chain. The 4-, 5- and 8-positions are preferred for the quinolinering, and the 1-position is preferred for the isoquinoline ring.

The subject matter of the invention includes the compounds of generalformula I, in which

-   A stands for an aryl group, a benzyl group or a phenethyl group,    whereby the aryl, benzyl or phenethyl group optionally can be    substituted by one or more radicals from the group C₁-C₅-alkyl,    C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-perfluoroalkyl, halogen,    hydroxy, cyano, nitro, —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—,    —O—CH═CH—, or —(CH₂)_(n+2)—, whereby n=1 or 2, and the terminal    oxygen atoms and/or carbon atoms are linked with directly adjacent    ring-carbon atoms, or NR⁴R⁵,    -   whereby R⁴ and R⁵, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,-   R¹ and R², independently of one another, mean a hydrogen atom, a    methyl or ethyl group or together with the carbon atom mean the    chain of a C₃-C₆-cycloalkyl ring,-   R³ means a C₁-C₃-alkyl group or a C₁-C₃-alkyl group that is    optionally partially or completely fluorinated,-   B means a methylene group that is optionally substituted by a methyl    or ethyl group, or a carbonyl group, and-   Q means a quinolinyl group or isoquinolinyl group that is linked via    any position and that optionally can be substituted by one or more    radicals from the group C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,    C₁-C₅-perfluoroalkyl, halogen, hydroxy, cyano, nitro or NR⁴R⁵,    -   whereby R⁴ and R⁵, independently of one another, can be        hydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl,        as well as their racemates or separately present stereoisomers        and optionally their physiologically compatible salts.

The subject matter of the invention includes compounds of generalformula I in which Q means a quinolinyl group or an isoquinolinyl groupthat is linked via any position and that optionally can be substitutedby one or more radicals from the group C₁-C₅-alkyl, which optionally canbe substituted by 1-3 hydroxy groups or 1-3 COOR⁶ groups,

-   a carbonyl-oxygen atom,-   COOR⁶, whereby R⁶ means hydrogen or a C₁-C₅-alkyl group,-   (CO)NR⁷R⁸, whereby R⁷ and R⁸, independently of one another, mean    hydrogen or a C₁-C₅-alkyl group,-   or a (C₁-C₅-alkyl)-O—(CO)—(C₁-C₅)alkyl group.

The subject matter of the invention includes compounds of generalformula I in which Q represents a quinolinyl group that is substitutedin one place.

The subject matter of the invention includes compounds in which B meansa methylene group and Q means an optionally substituted quinolinylgroup.

The subject matter of the invention includes compounds in which A meansan optionally substituted phenyl group, Q means an optionallysubstituted quinolinyl group, and B means a methylene group.

The compounds of general formula I according to the invention can bepresent as different stereoisomers by the presence of asymmetry centers.Both the racemates and the separately present stereoisomers are part ofthe subject of this invention.

A special subject of this invention are the separately presentstereoisomers, i.e., (+)-enantiomers and (−)-enantiomers.

The compounds according to the invention, if they contain a hydroxygroup in α-position to the quinolinyl or isoquinolinyl-nitrogen atom,are also distinguished by the presence of a keto-enol-tautomerism. Interms according to the invention, both forms are part of the subject ofthe invention, even if, e.g., in the experimental part, only one of thetwo tautomeric forms has been cited.

The process for the production of the compounds of WO98/54159,WO00/32584 and WO02/10143 can also be used for the production of thecompounds according to the invention. For the linkage of the quinolineor isoquinoline group that is characteristic of the compounds accordingto the invention, the following process steps can be implemented:

A1)

-   For B═CO

An α-keto acid of general formula (II), in which A, R¹ and R² have themeanings that are indicated for formula (I), is converted with anaminoquinoline, an aminoisoquinoline or a (partially)hydrogenatedquinoline or isoquinoline derivative (Q-NH₂) into α-ketoamide (III),whereby A, R¹, and R² have the above-indicated meaning, in the way thatis known to one skilled in the art. For example, α-ketoamide (III) isobtained with use of dehydrating coupling reagents, as they are knownfrom peptide chemistry, e.g., dicyclohexylcarbodiimide, or by upstreamconversion of the acid into an acid chloride, e.g., with thionylchloride or POCl₃ and subsequent reaction with Q-NH₂.

Compound (III) is reacted either with an alkyl metal compound, forexample a Grignard reagent or a lithium alkyl, or by reaction withcompound (IV),

 (R⁹)₃Si—R³  (IV)

whereby R³ has the above-indicated meaning and R⁹ refers to aC₁-C₅-alkyl group, in the presence of a catalyst, e.g., fluoride saltsor bases, such as, for example, alkali carbonates (J. Am. Chem. Soc.1989, 111, 393) to form title compound (I).

A2)

-   For B═CO    -   [Key: 1. verestern=1. esterification]        As an alternative, α-keto acids (II) can also be esterified to        compounds (V)        in which A, R¹, and R² are defined as described above and R¹⁰ is        C₁-C₄-alkyl, according to commonly used methods, e.g., with        thionyl chloride in methanol or ethanol or with methyl iodide        and alkali carbonate, and can be converted from (III) to (I) in        compound (VI) analogously to reaction sequence A1).

The ester is saponified under standard conditions, for example aqueousalkali hydroxide solution, to acid (VI; R¹⁰=H). The latter is reacted inthe coupling with an aminoquinoline or aminoisoquinoline or a(partially)-hydrogenated quinoline or isoquinoline derivative (Q-NH₂)with use of a standard activating reagent, e.g., thionyl chloride,optionally in the presence of a catalyst such as dimethylaminopyridine,to form title compound (I).

B)

-   For B=a methylene group that is optionally substituted by methyl or    ethyl    a)

A compound of general formula (VII) or (VIII),

in which A, B and R¹, R², and R³ have the above-indicated meaning, andLG means any leaving group such as halide or sulfonate, is reacted witha compound of general formula (IX) or (X)Q—NH—R¹²  (IX)Q—N═C═O  (X)in which R¹² means a hydrogen atom, a C₁-C₅-acyl group or alkoxy- oraryloxycarbonyl group, and Q has the above-indicated meaning, wherebyradical R¹² is cleaved off or an intermediately formed oxazolidinone(cf., e.g., S. J. Brickner, D. K. Hutchinson, M. R. Barbachyn, P. R.Manninen, D. A. Ulanowicz, S. A. Garmon, K. C. Grega, S. K. Hendges, D.S. Toops, C. W. Ford, G. E. Zurenko J. Med. Chem. 1996, 39, 673) iscleaved with, for example, aqueous alkali hydroxides to obtain titlecompound (I).b)

Another method consists in reacting compounds of formula (VII) or (VIII)with nitrogen nucleophiles, for example acid salts or ammonia, wherebyin the first case, a reduction follows in the way that is known to oneskilled in the art, e.g., with complex hydride reagents, such as lithiumaluminum hydride, or by a transition metal-catalyzed hydrogenolysis toobtain compounds of formula (XI).

As indicated above, radicals R¹-R³, A and B are equally important.

c)

Compound (XI) can be converted under base catalysis, e.g., in thepresence of tertiary amine bases or alkali carbonates or alkalihydroxides, or under transition-metal catalysis, e.g., palladiumcatalysis (J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald Acc.Chem. Res. 1998, 31, 805; J. F. Hartwig Acc. Chem. Res. 1998, 31, 852),with a halogenated quinoline or isoquinoline into title compound (I).

d)

Finally, title compound (I) can also be synthesized by reductiveamination of a compound of formula (XII) with Q-NH₂, whereby, e.g.,sodium cyanoborohydride or sodium triacetoxy borohydride can beconsidered as a reducing agent.

R¹¹ means methyl or ethyl according to the substituents that are definedfor the methylene group in B.

In the case that the compounds of general formula I are present assalts, this can be, for example, in the form of hydrochloride, sulfate,nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate,mesylate, citrate or succinate.

If the compounds according to the invention are present as racemicmixtures, they can be separated into the pure, optically active formsaccording to the methods of racemate separation that are familiar to oneskilled in the art. For example, the racemic mixtures can be separatedinto pure isomers by chromatography on an even optically active carriermaterial (CHIRALPAK AD®). It is also possible to esterify the freehydroxy group in a racemic compound of general formula I with anoptically active acid and to separate the diastereoisomeric esters thatare obtained by fractionated crystallization or by chromatography and tosaponify the separated esters in each case to the optically pureisomers. As optically active acid, for example, mandelic acid,camphorsulfonic acid or tartaric acid can be used.

The binding of the substances to the glucocorticoid receptor (GR) andother steroid hormone receptors (mineral corticoid receptor (MR),progesterone receptor (PR) and androgen receptor (AR)) is examined withthe aid of recombinantly produced receptors. Cytosol preparations of Sf9cells, which had been infected with recombinant baculoviruses that codefor the GR, are used for the binding studies. In comparison to thereference substance [³H]-dexamethasone, the substances show a high tovery high affinity to GR.

Moreover, the quinolines and isoquinolines of formula (I) that aredescribed here show a high selectivity for the glucocorticoid receptor.Example 4 thus shows, e.g., the following profile: IC₅₀(GR)=0.6-1.3 nM;IC₅₀(MR), IC₅₀(PR), IC₅₀(AR)>1 μM.

The GR-mediated inhibition of the transcription of cytokines, adhesionmolecules, enzymes and other pro-inflammatory factors is considered asan essential, molecular mechanism for the anti-inflammatory action ofglucocorticoids. This inhibition is produced by an interaction of the GRwith other transcription factors, e.g., AP-1 and NF-kappa-B (for anoverview, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378, 1996).

The compounds of general formula I according to the invention inhibitthe secretion of the cytokine IL-8, triggered by lipopolysaccharide(LPS), in the human monocyte cell line THP-1. The concentration of thecytokines was determined in the supernatant by means of commerciallyavailable ELISA kits.

The anti-inflammatory action of the compounds of general formula I wastested in the animal experiment by tests in the croton-oil-inducedinflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). Tothis end, croton oil in ethanolic solution was administered topically tothe animals' ears. The test substances were also administered topicallyor systemically at the same time or two hours before the croton oil.After 16-24 hours, the ear weight was measured as a measurement for theinflammatory edema, the peroxidase activity as a measurement for theinvasions of granulocytes and the elastase activity as a measurement forthe invasion of neutrophilic granulocytes. In this test, the compoundsof general formula I inhibit the three above-mentioned inflammationparameters both after topical administration and after systemicadministration.

One of the most frequent undesirable actions of a glucocorticoid therapyis the so-called “steroid diabetes” [cf. Hatz, H. J., Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[Glucocorticoids: Immunological Principles, Pharmacology and TherapyGuidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,1998]. The reason for this is the stimulation of gluconeogenesis in theliver by induction of the enzymes that are responsible for this and byfree amino acids that are produced from the degradation of proteins(catabolic action of glucocorticoids). A key enzyme of the catabolicmetabolism in the liver is the tyrosine aminotransferase (TAT). Theactivity of this enzyme can be determined photometrically from liverhomogenates and represents a good measurement for the undesirablemetabolic actions of the glucocorticoids. For measurement of TATinduction, the animals are sacrificed 8 hours after the test substancesare administered, the livers are removed, and the TAT activity in thehomogenate is measured. In this test, at doses at which they have ananti-inflammatory action, the compounds of general formula I inducelittle or no tyrosine aminotransferase.

Based on their anti-inflammatory action and, in addition, anti-allergic,immunosuppressive and anti-proliferative action, the compounds ofgeneral formula I according to the invention can be used as medicationsfor treatment or prophylaxis of the following pathologic conditions inmammals and humans: In this case, the term “DISEASE” stands for thefollowing indications:

-   (i) Lung diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Chronic, obstructive lung diseases of any origin, primarily        bronchial asthma    -   Bronchitis of different origins    -   All forms of restrictive lung diseases, primarily allergic        alveolitis,    -   All forms of pulmonary edema, primarily toxic pulmonary edema    -   Sarcoidoses and granulomatoses, especially Boeck's disease-   (ii) Rheumatic diseases/autoimmune diseases/joint diseases that are    accompanied by inflammatory, allergic and/or proliferative    processes:    -   All forms of rheumatic diseases, especially rheumatoid        arthritis, acute rheumatic fever, polymyalgia rheumatica    -   Reactive arthritis    -   Inflammatory soft-tissue diseases of other origins    -   Arthritic symptoms in the case of degenerative joint diseases        (arthroses)    -   Traumatic arthritides    -   Collagenoses of any origin, e.g., systemic lupus erythematodes,        sclerodermia, polymyositis, dermatomyositis, Sjögren's syndrome,        Still's syndrome, Felty's syndrome-   (iii) Allergies that are accompanied by inflammatory and/or    proliferative processes:    -   All forms of allergic reactions, e.g., Quincke's edema, hay        fever, insect bites, allergic reactions to pharmaceutical        agents, blood derivatives, contrast media, etc., anaphylactic        shock, urticaria, contact dermatitis-   (iv) Vascular inflammations (vasculitides)    -   Panarteritis nodosa, arteritis temperalis, erythema nodosum-   (v) Dermatological diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Atopic dermatitis (primarily in children)    -   Psoriasis    -   Pityriasis rubra pilaris    -   Erythematous diseases, triggered by different noxae, e.g.,        radiation, chemicals, burns, etc.    -   Bullous dermatoses    -   Diseases of the lichenoid group,    -   Pruritis (e.g., of allergic origin)    -   Seborrheal eczema    -   Rosacea    -   Pemphigus vulgaris    -   Erythema exudativum multiforme    -   Balanitis    -   Vulvitis    -   Hair loss such as alopecia areata    -   Cutaneous T-cell lymphoma-   (vi) Kidney diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Nephrotic syndrome    -   All nephritides-   (vii) Liver diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Acute liver cell decomposition    -   Acute hepatitis of different origins, e.g., viral, toxic,        pharmaceutical agent-induced    -   Chronic aggressive hepatitis and/or chronic intermittent        hepatitis-   (viii) Gastrointestinal diseases that are accompanied by    inflammatory, allergic and/or proliferative processes:    -   Regional enteritis (Crohn's disease)    -   Colitis ulcerosa    -   Gastritis    -   Reflux esophagitis    -   Ulcerative colitis of other origins, e.g., native sprue-   (ix) Proctologic diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Anal eczema    -   Fissures    -   Hemorrhoids    -   Idiopathic proctitis-   (x) Eye diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Allergic keratitis, uveitis, iritis    -   Conjunctivitis    -   Blepharitis    -   Optic neuritis    -   Chorioiditis    -   Sympathetic ophthalmia-   (xi) Diseases of the ear-nose-throat area that are accompanied by    inflammatory, allergic and/or proliferative processes:    -   Allergic rhinitis, hay fever    -   Otitis extema, e.g., caused by contact dermatitis, infection,        etc.    -   Otitis media-   (xii) Neurological diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Cerebral edema, primarily tumor-induced cerebral edema    -   Multiple sclerosis    -   Acute encephalomyelitis    -   Meningitis    -   Various forms of convulsions, e.g., infantile nodding spasms-   (xiii) Blood diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Acquired hemolytic anemia    -   Idiopathic thrombocytopenia-   (xiv) Tumor diseases that are accompanied by inflammatory, allergic    and/or proliferative processes:    -   Acute lymphatic leukemia    -   Malignant lymphoma    -   Lymphogranulomatoses    -   Lymphosarcoma    -   Extensive metastases, mainly in breast, bronchial and prostate        cancers-   (xv) Endocrine diseases that are accompanied by inflammatory,    allergic and/or proliferative processes:    -   Endocrine orbitopathy    -   Thyreotoxic crisis    -   De Quervain's thyroiditis    -   Hashimoto's thyroiditis    -   Basedow's disease-   (xvi) Organ and tissue transplants, graft-versus-host disease-   (xvii) Severe shock conditions, e.g., anaphylactic shock, systemic    inflammatory response syndrome (SIRS)-   (xviii) Substitution therapy in:    -   Innate primary suprarenal insufficiency, e.g., congenital        adrenogenital syndrome    -   Acquired primary suprarenal insufficiency, e.g., Addison's        disease, autoimmune adrenalitis, meta-infective tumors,        metastases, etc.    -   Innate secondary suprarenal insufficiency, e.g., congenital        hypopituitarism    -   Acquired secondary suprarenal insufficiency, e.g.,        meta-infective tumors, etc.-   (xix) Vomiting that is accompanied by inflammatory, allergic and/or    proliferative processes:-   e.g., in combination with a 5-HT3 antagonist in    cytostatic-agent-induced vomiting-   (xx) Pains of inflammatory origins, e.g., lumbago.

Moreover, the compounds of general formula I according to the inventioncan be used for treatment and prophylaxis of additional pathologicconditions that are not mentioned above, for which syntheticglucocorticoids are now used (see in this respect Hatz, H. J.,Glucocorticoide: Immunologische Grundlagen, Pharmakologie undTherapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart, 1998).

All previously mentioned indications (i) to (xx) are described in moredetail in Hatz, H. J., Glucocorticoide: Immunologische Grundlagen,Pharmakologie und Therapierichtlinien, WissenschaftlicheVerlagsgesellschaft mbH, Stuttgart, 1998.

For the therapeutic actions in the above-mentioned pathologicconditions, the suitable dose varies and depends on, for example, theactive strength of the compound of general formula I, the host, the typeof administration, and the type and severity of the conditions that areto be treated, as well as the use as a prophylactic agent or therapeuticagent.

The invention additionally provides:

-   -   (i) The use of one of the compounds of general formula I        according to the invention or mixture thereof for the production        of a medication for treating a DISEASE;    -   (ii) A process for treating a DISEASE, said process comprises an        administration of an amount of the compound according to the        invention whereby the amount suppresses the disease and whereby        the amount of compound is given to a patient who requires such a        medication;    -   (iii) A pharmaceutical composition for treating a DISEASE, said        treatment comprises one of the compounds according to the        invention or mixture thereof and at least one pharmaceutical        adjuvant and/or vehicle.

In general, satisfactory results can be expected in animals when thedaily doses comprise a range of 1 μg to 100,000 μg of the compoundaccording to the invention per kg of body weight. In the case of largermammals, for example the human, a recommended daily dose lies in therange of 1 μg to 100,000 μg per kg of body weight. Preferred is a doseof 10 to 30,000 μg per kg of body weight, and more preferred is a doseof 10 to 10,000 μg per kg of body weight. For example, this dose issuitably administered several times daily. For treating acute shock(e.g., anaphylactic shock), individual doses can be given that aresignificantly above the above-mentioned doses.

The formulation of the pharmaceutical preparations based on the newcompounds is carried out in a way that is known in the art by the activeingredient being processed with the vehicles that are commonly used ingalencials, fillers, substances that influence decomposition, bindingagents, moisturizers, lubricants, absorbents, diluents, flavoringcorrectives, coloring agents, etc., and converted into the desired formof administration. In this case, reference is made to Remington'sPharmaceutical Science, 15^(th) Edition, Mack Publishing Company, EastPennsylvania (1980).

For oral administration, especially tablets, coated tablets, capsules,pills, powders, granulates, lozenges, suspensions, emulsions orsolutions are suitable.

For parenteral administration, injection and infusion preparations arepossible.

For intra-articular injection, correspondingly prepared crystalsuspensions can be used.

For intramuscular injection, aqueous and oily injection solutions orsuspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form ofsuppositories, capsules, solutions (e.g., in the form of enemas) andointments both for systemic and for local treatment.

For pulmonary administration of the new compounds, the latter can beused in the form of aerosols and inhalants.

For local application to eyes, outer ear channels, middle ears, nasalcavities, and paranasal sinuses, the new compounds can be used as drops,ointments and tinctures in corresponding pharmaceutical preparations.

For topical application, formulations in gels, ointments, fattyointments, creams, pastes, powders, milk and tinctures are possible. Thedosage of the compounds of general formula I should be 0.01%-20% inthese preparations to achieve a sufficient pharmacological action.

The invention also comprises the compounds of general formula Iaccording to the invention as therapeutic active ingredients. Inaddition, the compounds of general formula I according to the inventionare part of the invention as therapeutic active ingredients togetherwith pharmaceutically compatible and acceptable adjuvants and vehicles.

The invention also comprises a pharmaceutical composition that containsone of the pharmaceutically active compounds according to the inventionor mixture thereof or pharmaceutically compatible salt thereof and apharmaceutically compatible salt or pharmaceutically compatibleadjuvants and vehicles.

The examples below are used for a more detailed explanation of theinvention without intending that it be limited thereto. The syntheses ofimportant precursors, which are not disclosed within the scope of theexperiments, are already prior art and can be derived from, for example,WO 98/54159 and WO 02/10143.

EXPERIMENTS Example 1

1-(Quinolin-8-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

200 mg (0.68 mmol) of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl)-2-(trifluoromethyl)oxirane(WO 00/32584) and 99 mg (0.68 mmol) of 8-aminoquinoline are heated in0.2 ml of 3,4,5,6-tetrahydro-2-(1H)-pyrimidone (DMPU) for 20 hours to130° C. After the reaction mixture is purified on silica gel withhexane-ethyl acetate (0-20%), 230 mg of the product is obtained.

¹H-NMR (CDCl₃): δ=1.47 (s, 3H), 1.65 (s, 3H), 2.25 (d, 1H), 2.85 (d,1H), 3.30 (AB-system, 2H), 3.85 (s, 3H), 6.13 (br., d, 1H), 6.80 (dd,1H), 6.95 (ddd, 1H), 7.13 (d, 1H), 7.20 (dd, 1H), 7.32 (z, 1H), 7.45 (m,1H), 8.18 (m, 1H), 8.72 (dd, 1H).

Example 2

1-(Quinolin-8-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

200 mg (0.46 mmol) of1-(quinolin-8-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 20 ml of CH₂Cl₂ is mixed at 0° C. with 9 ml of 1 M borontribromide-CH₂Cl₂ solution. After 20 hours at room temperature, thebatch is poured into saturated NaHCO₃ solution, stirred for 20 minutesand extracted with CH₂Cl₂. The combined organic extracts are washed withwater, dried (Na₂SO₄) and concentrated by evaporation in a vacuum.Chromatography with hexane-ethyl acetate (0-25%) on silica gel yields190 mg of the product.

¹H-NMR (CDCl₃): δ=1.48 (s, 3H), 1.62 (s, 3H), 2.20 (d, 1H), 3.18 (d,1H), 3.35 (s, 2H), 6.45 (d, 1H), 6.52 (dd, 1H), 6.65 (ddd, 1H), 7.08(dd, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 7.50 (dd, 1H), 8.25 (d, 1H), 8.83(dd, 1H).

Example 3

1-(Quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 1, 200 mg (0.48 mmol) of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxiraneis reacted with 99 mg (0.68 mmol) of 5-aminoquinoline. Afterchromatography on silica gel with hexane-ethyl acetate (0-70%), 58 mg ofthe product is obtained.

¹H-NMR (CDCl₃): δ=1.47 (s, 3H), 1.56 (s, 3H), 2.38 (d, 1H), 2.78 (d,1H), 3.15 (dd, 1H), 3.33 (dd, 1H), 3.85 (s, 3H), 4.65 (br., 1H), 6.10(d, 1H), 6.80 (dd, 1H), 6.93 (ddd, 1H), 7.10 (dd, 1H), 7.37 (dd, 1H),7.50 (t, 1H), 7.61 (d, 1H), 8.18 (d, 1H), 6.80 (dd, 1H).

Example 4

1-(Quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 2, 58 mg (0.13 mmol) of1-(quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 6 ml of CH₂Cl₂ is reacted with 2.6 ml of 1 M boron tribormide-CH₂Cl₂solution. After chromatography on silica gel with hexane-ethyl acetate(0-70%), 22 mg of the product is obtained.

¹H-NMR (CDCl₃): δ=1.48 (s, 3H), 1.54 (s, 3H), 2.45 (d, 1H), 2.82 (d,1H), 3.20 (dd, 1H), 3.40 (dd, 1H), 5.05 (br., 1H), 6.25 (d, 1H), 6.70(m, 1H), 6.85 (dd, 1H), 6.95 (dd, 1H), 7.45 (dd, 1H), 7.53 (d, 1H), 7.58(d, 1H), 8.32 (d, 1H), 8.68 (d, 1H).

Example 5

1-(Quinolin-4-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

1-Amino-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)propan-2-ol

1.0 g (3.4 mmol) of2-[2-(5-fluoro-2-methoxyphenyl-2-methylpropyl]-2-(trifluoromethyl)oxiranein 68 ml of THF is refluxed with 1.1 g of sodium azide and 180 mg ofammonium chloride in 14 ml of water and 26 ml of ethanol for 6 hours.The batch is concentrated by evaporation, diluted with ether, washedwith water, dried (Na₂SO₄) and concentrated by evaporation.Chromatography on silica gel with hexane-ethyl acetate (0-15%) yields950 mg of1-azido-4-(5-fluoro-2-methoxphenyl)-4-methyl-2-(trifluoromethyl)propan-2-ol.The latter is dissolved in 29 ml of THF and mixed in portions at 0° C.with 270 mg of lithium aluminum hydride. After 1 hour, the batch istreated with ethyl acetate and water and filtered on Celite. The ethylacetate phase is dried (Na₂SO₄) and concentrated by evaporation in avacuum. 920 mg of amine is obtained.

¹H-NMR (CDCl₃): δ=1.4 (s, 3H), 1.5 (s, 3H), 2.15 (d, 1H), 2.45 (d, 1H),2.55 (d, 1H), 2.75 (d, 1H), 2.80 (m), 3.8 (s, 3H), 6.8 (dd, 1H), 6.9(td, 1H), 7.05 (dd, 1H).

1-(Quinolin-4-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

500 mg (1.6 mmol) of1-amino-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)propan-2-ol,265 mg (1.6 mmol) of 4-chloroquinoline and 183 mg (1.6 mmol) ofdiazabicyclo-[2.2.2]octane are heated for 3 hours to 150° C. The batchis dissolved in CH₂Cl₂ and water. The aqueous phase is extracted withCH₂Cl₂, the combined organic extracts are washed with water, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Chromatography onsilica gel with CH₂Cl₂-methanol (0-10%) yields 305 mg of product.

¹H-NMR (D₆-DMSO): δ=1.40 (s, 3H), 1.57 (s, 3H), 2.10 (d, 1H), 2.88 (d,1H), 3.05 (dd, 1H), 3.15 (dd, 1H), 3.80 (s, 3H), 5.96 (d, 1H), 6.00 (s,1H), 6.26 (br. t, 1H), 6.98 (d, 1H), 7.02 (td, 1H), 7.10 (dd, 1H), 7.45(t, 1H), 7.60 (t, 1H), 7.77 (d, 1H), 7.95 (d, 1H), 8.30 (d, 1H).

Example 6

1-(Quinolin-4-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 2, 200 mg (0.46 mmol) of1-(quinolin-4-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-oland 9 ml of 1 M boron tribromide-CH₂Cl₂ solution are reacted. Afterchromatography on silica gel with CH₂Cl₂-methanol (0-15%), 138 mg ofproduct is obtained.

¹H-NMR (D₆-DMSO): δ=1.40 (s, 3H), 1.58 (s, 3H), 1.95 (d, 1H), 3.00-3.50(m, 3H), 6.05 (m+d, 2H), 6.65 (br., 1H), 6.80 (dd, 1H), 6.86 (td, 1H),7.05 (dd, 1H), 7.50 (t, 1H), 7.65 (t, 1H), 7.80 (d, 1H), 8.02 (d, 1H),8.32 (d, 1H), 9.82 (br., 1H).

Example 7

4-(5-Fluoro-2-methoxyphenyl)-1-(isoquinolin-1-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 1, 200 mg (0.68 mmol) of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxiraneand 99 mg (0.68 mmol) of 1-aminoisoquinoline are reacted. Afterchromatography on silica gel with hexane-ethyl acetate (0-60%), 65 mg ofproduct is obtained.

¹H-NMR (CDCl₃): δ=1.45 (s, 3H), 1.72 (s, 3H), 2.40 (d, 1H), 3.00 (d,1H), 3.40 (d, 1H), 3.88 (s, 3H), 4.23 (d, 1H), 6.40 (d, 1H), 6.63 (d,1H), 6.82 (dd, 1H), 6.89 (td, 1H), 7.15 (dd, 1H), 7.45 (d, 1H), 7.55 (t,1H), 7.65 (t, 1H), 8.45 (br., 1H).

Example 8

4-(5-Fluoro-2-hydroxyphenyl)-1-(isoquinoline-1-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 2, 65 mg (0.15 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(isoquinolin-1-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olis reacted with 2.7 ml of 1 M boron tribromide-CH₂Cl₂ solution. Afterchromatography on silica gel with hexane-ethyl acetate (0-80%), 33 mg ofthe product is obtained.

¹H-NMR (CDCl₃): δ=1.40 (s, 3H), 1.60 (s, 3H), 2.00 (d, 1H), 2.87 (d,1H), 3.53 (d, 1H), 4.23 (d, 1H), 6.25 (d, 1H), 6.70-6.90 (m, 3H), 7.00(dd, 1H), 7.42 (t, 1H), 7.48 (d, 1H), 7.58 (t, 1H), 8.05 (br., 1H), 8.22(d, 1H), 9.80 (br., 2H).

Example 9

1-(Quinolin-5-ylamino)-4-methyl-4-phenyl-2-(trifluoromethyl)pentan-2-ol

2-(2-Methyl-2-phenylpropyl)-2-(trifuoromethyl)oxirane

10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159) in 250 mlof dimethylformamide is mixed at −5° C. with 4.1 ml of thionyl chlorideand after 15 minutes with 4 ml of methanol. After 15 hours at roomtemperature, the batch is diluted with water and extracted with ethylacetate. The organic extracts are washed with water, dried (Na₂SO₄) andconcentrated by evaporation, whereby 9.3 g of4-methyl-2-oxo-4-phenylpentanoic acid-methyl ester is obtained. Thelatter is mixed in 558 ml of DMF at −5° C. with 15.5 ml (104.63 mmol) of(trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesiumcarbonate and stirred for 16 hours at room temperature. Water is added,extracted with ethyl acetate, the organic phase is washed with water anddried (Na₂SO₄). The intermediate product that is concentrated byevaporation is taken up in 200 ml of THF and 50 ml of a 1 M solution oftetrabutylammonium fluoride in THF is added. It is stirred for 2 hours,water is added, extracted with ethyl acetate, the organic phase iswashed with water and dried (Na₂SO₄). After chromatography on silica gelwith hexane-ethyl acetate (0-30%), 8.35 g of2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid-methylester is obtained. The ester (8.3 g, 28.59 mmol) is dissolved in 180 mlof THF, and 1.52 g (36.20 mmol) of lithium aluminum hydride is added insmall portions over a period of 2.5 hours. After complete conversion, 5ml of ethyl acetate is added in drops, and after another 10 minutes, 10ml of water is carefully added. The formed precipitate is filtered outand washed carefully with ethyl acetate. After chromatography on silicagel with hexane-ethyl acetate (0-35%), 5.40 g of4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.6 g(21.35 mmol) of triphenylphosphine and, while being cooled with ice, 4.3ml (27.31 mmol) of azodicarboxylic acid-diethyl ester are added to diol(5.40 g, 20.59 mmol) in 43 ml of THF. The reaction mixture is refluxedfor 3 hours and, after cooling, it is concentrated by evaporation. Afterchromatography on silica gel with hexane-ethyl acetate (0-15%), 4.18 gof product is obtained.

¹H-NMR (CDCl₃): δ=1.37 (s, 3H), 1.41 (s, 3H), 2.20 (m, 1H), 2.27 (d,1H), 2.55 (d, 1H), 2.67 (d, 1H), 7.18-7.35 (m, 5H).

1-(Quinolin-5-ylamino)-4-methyl-4-phenyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 1, 300 mg (1.22 mmol) of2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 882 mg (6.12mmol) of 5-aminoquinoline are reacted. After chromatography on silicagel with hexane-ethyl acetate (0-75%), 85 mg of product is obtained.

¹H-NMR (CDCl₃): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.30 (d, 1H), 2.36 (d,1H), 3.02 (dd, 1H), 3.05 (s, 1H), 3.25 (dd, 1H), 4.24 (dd, 1H), 6.11 (d,1H), 7.28-7.56 (m, 8H), 8.04 (d, 1H), 8.86 (dd, 1H).

Example 10

4-Methyl-1-(2-methylquinolin-5-ylamino)-4-phenyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 1, 500 mg (2.05 mmol) of2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 650 mg (4.10mmol) of 5-amino-2-methylquinoline are reacted. After chromatography onsilica gel with hexane-ethyl acetate (0-70%), 485 mg of product isobtained.

¹H-NMR (CDCl₃): δ=1.44 (s, 3H), 1.59 (s, 3H), 2.30 (d, 1H), 2.35 (d,1H), 2.72 (s, 3H), 3.01 (dd, 1H), 3.04 (s, 1H), 3.23 (dd, 1H), 4.18 (dd,1H), 6.04 (d, 1H), 7.21 (d, 1H), 7.30 (dt, 1H), 7.37-7.51 (m, 6H), 7.92(d, 1H).

Example 11

N-(Quinolin-5-yl)-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoicacid amide

540 mg (2.13 mmol) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid (WO 00/32584)in 15 ml of DMF is mixed at −5° C. under argon with 0.18 ml of thionylchloride. After 20 minutes of stirring at −3° C. to +3° C., 470 mg (3.26mmol) of 5-aminoquinoline is added. It is allowed to heat to roomtemperature, stirred for another 16 hours, mixed with 10% citric acid,extracted with ethyl acetate, the organic phase is washed with water anddried (Na₂SO₄). After chromatography on silica gel with hexane-ethylacetate (0-75%), 680 mg ofN-(quinolin-4-yl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentanoicacid amide is obtained, which is dissolved in 22 ml of DMF and cooled to0° C. The solution is mixed with 1.80 ml of(trifluoromethyl)trimethylsilane and 2.43 g of cesium carbonate andstirred for 16 hours at room temperature. Water is added, extracted withethyl acetate, the organic phase is washed with water and dried onsodium sulfate. The intermediate product that is concentrated byevaporation is taken up in 10 ml of THF, and 5.5 ml of a 1 M solution oftetrabutylammonium fluoride is added. It is stirred for 1.5 hours, wateris added, extracted with ethyl acetate, the organic phase is washed withwater and dried on sodium sulfate. After chromatography on silica gelwith hexane-ethyl acetate (0-70%), 420 mg of product is obtained.

¹H-NMR (CDCl₃): δ=1.44 (s, 3H), 1.46 (s, 3H), 2.80 (d, 1H), 3.10 (d,1H), 3.57 (s, 1H), 3.89 (s, 3H), 6.81 (dd, 1H), 6.89 (m, 1H), 6.99 (dd,1H), 7.45 (dd, 1H), 7.73 (t, 1H), 7.95 (d, 1H), 7.99 (d, 1H), 8.00 (d,1H), 8.83 (br., 1H), 8.95 (dd, 1H).

Example 12

4-(1,3-Benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

1,3-Benzodioxol-4-carboxylic acid-methyl ester:

50 g of 2,3-dihydroxybenzoic acid in 450 ml of methanol is mixed at roomtemperature drop by drop with 50 ml of thionyl chloride. Then, thesolution is heated for 5 hours to 60° C. and stirred overnight at roomtemperature. The solvent is completely removed in a vacuum, and theremaining oil is taken up in diethyl ether and extracted with saturatedbicarbonate solution. After washing with brine, drying with sodiumsulfate and removal of the solvent in a vacuum, 46 g of2,3-dihydroxybenzoic acid methyl ester is obtained. The latter is mixedin 575 ml of DMF and 20.2 ml of dibromomethane with 56.7 g of potassiumcarbonate, and it is heated for 5 hours under argon to 100° C. Then, itis stirred overnight at room temperature. It is then mixed with waterand extracted three times with ethyl acetate. The organic phase iswashed several times with water and dried on sodium sulfate. The solventis removed in a vacuum, and 50.2 g of 1,3-benzodioxole-4-carboxylicacid-methyl ester is obtained as a brown solid. Flash point: 55-57° C.

4-(1,3-Benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid

4.76 g of 1,3-benzodioxole-4-carboxylic acid-methyl ester in 65 ml ofdry THF is added in drops at room temperature to a solution of 21 ml of3 M methylmagnesium chloride in THF under argon. It is stirred for 3hours and then slowly mixed with 1N hydrochloric acid. After extractionwith ethyl acetate and after the organic phase is washed with water, itis dried with sodium sulfate, and the solvent is removed in a vacuum.5.0 g of 1-(1,3-benzodioxol-4-yl)-1-methyl ethanol is obtained as abrown oil. 3.6 g and 5.4 g of 2-(trimethylsilyloxy)-acrylic acid ethylester in 80 ml of dichloromethane are mixed at −70° C. with 18 ml of tintetrachloride. After 15 minutes of stirring at −70° C., the solution ispoured onto semi-saturated sodium carbonate solution, mixed with ethylacetate and vigorously stirred. The phases are separated, and the waterphase is extracted twice with ethyl acetate. The organic phase is washedwith brine, dried with sodium sulfate, and the solvent is removed in avacuum. A yellow oil that is mixed with 60 ml of 1N sodium hydroxidesolution and 120 ml of methanol and stirred for 3 hours at roomtemperature is obtained. The methanol is removed in a vacuum, and thewater phase is extracted with diethyl ether. Then, the water phase isacidified by adding 120 ml of 1N hydrochloric acid and extracted 3 timeswith diethyl ether. The ether phase is dried, and the solvent is removedin a vacuum. 4.2 g of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoicacid is obtained as a yellow oil. MS (EI): M⁺=250 (M=250)

4-(1,3-Benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide

100 mg of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid in 1 mlof dimethyl acetamide is mixed at 0° C. with 0.034 ml of thionylchloride and stirred for 20 minutes. Then, 61 mg of 5-aminoquionoline isadded, and it is stirred overnight at room temperature. It is added tosodium bicarbonate solution and extracted 3 times with ethyl acetate. Itis washed with brine, dried, and the solvent is removed in a vacuum. Theremaining oil is separated by thick-layer chromatography (silica gel,acetone/hexane 1:1). 25 mg of4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide isobtained as a yellow foam. MS (EI): M⁺=376.3 (M=376.4).

4-(1,3-Benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

22 mg of4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide and0.04 ml of trifluoromethyltrimethylsilane in 1 ml of DMF are mixed at 0°C. with 11 mg of cesium carbonate. After 2 hours, a spatula-tip full oftetrabutylammonium fluoride is added, and after another 20 minutes, thereaction is added to water. It is extracted 3 times with ethyl acetate,washed with water and brine, dried, and the solvent is removed in avacuum. The remaining oil is separated by chromatography on silica gel.11 mg of4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamideis obtained as a solid. Flash point: 164-167° C.

Example 13

N-(Quinolin-5-yl)-4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

N-(Quinolin-5-yl)-4-(2-chlorophenyl)-4-methyl-2-oxopentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamideafter chromatography on silica gel, 152 mg ofN-(quinolin-5-yl)-4-(2-chlorophenyl)-4-methyl-2-oxopentanamide isobtained from 200 mg of 4-(2-chlorophenyl)-4-methyl-2-oxopentanoic acid(WO00/32584). MS (EI): M⁺=366, 368 (3:1); (M=366.8).

N-(Quinolin-5-yl)-4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 82 mg ofN-(quinolin-5-yl)-4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamideis obtained from 142 mg ofN-(quinolin-5-yl)-4-(2-chlorophenyl)-4-methyl-2-oxopentanamide. Flashpoint: 210-214° C.

Example 14

N-(Quinolin-5-yl)-4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

N-(Quinolin-5-yl)-4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxopentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide(Example 12) after chromatography on silica gel, 400 mg ofN-(quinolin-5-yl)-4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxopentanamideis obtained from 520 mg of4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxopentanoic acid (WO 02/10143).Flash point: 145-146° C.

N-(Quinolin-5-yl)-4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 60 mg ofN-(quinolin-5-yl)-4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamideis obtained from 384 mg ofN-(quinolin-5-yl)-4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxopentanamide.Flash point 188-189° C.

Example 15

N-(Quinolin-5-yl)-3-[1-(2-chloro-4-fluorophenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanamide

N-(Quinolin-5-yl)-3-[1-(2-chloro-4-fluorophenyl)-cyclopropyl]-2-oxopropanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 535 mg ofN-(quinolin-5-yl)-3-[1-(2-chloro-4-fluorophenyl)-cyclopropyl]-2-oxopropanamideis obtained as a foam from 512 mg of3-[1-(2-chloro-4-fluorophenyl)-cyclopropyl]-2-oxopropionic acid (WO02/10143).

N-(Quinolin-5-yl)-3-[1-(2-chloro-4-fluorophenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 200 mg ofN-(quinolin-5-yl)-3-[1(-2-chloro-4-fluorophenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)pentanamideis obtained from 535 mg ofN-(quinolin-5-yl)-3-[1-(2-chloro-4-fluorophenyl)-cyclopropyl]-2-oxopropanamide.Flash point: 220-221° C.

Example 16

4-(4-Bromo-2-methoxyphenyl)-1-(quinolin-5-ylamino)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 1, 200 mg of2-[2-(4-bromo-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane(WO 00/32585) and 5-aminoquinoline are reacted. After chromatography onsilica gel with hexane-ethyl acetate (1+1), 43 mg of4-(4-bromo-2-methoxyphenyl)-1-(quinolin-5-ylamino)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-2-olis obtained. Flash point: 181° C.

Example 17

4-(5-Bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

1-(5-Bromo-2-methoxyphenyl)-1-methylethanol

62 ml of a 3 M methylmagnesium bromide solution in tetrahydrofuran isadded in drops within one hour at 0 C. into 18.6 g of5-bromo-2-methoxybenzoic acid methyl ester and 180 ml of diethyl ether.After 16 hours at room temperature and while being cooled with ice, itis mixed with saturated ammonium chloride solution and ethyl acetate.The ethyl acetate phase is washed with water, dried (Na₂SO₄) andconcentrated by evaporation. After bulb tube distillation (boilingpoint: 140° C./0.04 hPa), 16.7 g of crystalline1-(5-bromo-2-methoxyphenyl)-1-methylethanol is obtained. Flash point:66-68° C.

4-(5-Bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid-ethyl ester

9.8 g of 1-(5-bromo-2-methoxyphenyl)-1-methylethanol and 15.24 g of2-(trimethylsilyloxy)-acrylic acid ethyl ester in 150 ml ofdichloromethane are mixed at −70° C. with 5.6 ml of tin tetrachloride.After 20 minutes at −70° C., the solution is poured onto asemi-saturated potassium carbonate solution and mixed withdichloromethane. The dichloromethane phase is washed with potassiumcarbonate solution, 1 M hydrochloric acid and water, dried (Na₂SO₄) andconcentrated by evaporation. After bulb tube distillation, 5.2 g of4-(5-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid-ethyl ester isobtained. Boiling point: 160° C./0.04 hPa.

4-(5-Bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid

4-(5-Bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid-ethyl ester in30 ml of methanol and 12 ml of 1 M sodium hydroxide solution are stirredfor 1 hour at room temperature, and the methanol is distilled off. It ismixed with water and hexane, the water phase is acidified with dilutehydrochloric acid while being cooled with ice, and it is mixed withethyl acetate. The ethyl acetate phase is washed with water, dried(Na₂SO₄) and concentrated by evaporation. After crystallization fromhexane, 1.8 g of 4-(5-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoicacid is obtained. Flash point: 80° C.

4-(5-Bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide(Example 12) after chromatography on silica gel, 730 mg of4-(5-bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamideis obtained from 630 mg of4-(5-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid. Flash point:133-135° C.

4-(5-Bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 484 mg of4-(5-bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamideis obtained from 617 mg of4-(5-bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide.Flash point: 243-245° C.

Example 18

4-(4-Bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

4-(4-Bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide(Example 12) after chromatography on silica gel, 363 mg of4-(4-bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamideis obtained from 630 mg of4-(4-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid (WO 98/54159).Flash point: 114-115° C.

4-(4-Bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 280 mg of4-(4-bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamideis obtained from 528 mg of4-(4-bromo-2-methoxyphenyl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide.Flash point: 208-209° C.

Example 19

N-(Quinolin-5-yl)-)-2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanamide

N-(Quinolin-5-yl)-)-4-methyl-2-oxo-4-phenylpentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide(Example 12) after chromatography on silica gel, 370 mg ofN-(quinolin-5-yl)-)-4-methyl-2-oxo-4-phenylpentanamide is obtained from515 mg of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159). Flashpoint: 98-99° C.

N-(Quinolin-5-yl)-)-2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanamide

According to the instructions for4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanamide(Example 12) after chromatography on silica gel, 85 mg ofN-(quinolin-5-yl)-2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanamideis obtained from 200 mg ofN-(quinolin-5-yl)-4-methyl-2-oxo-4-phenylpentanamide. Flash point:181-182° C.

Example 20

4-(5-Fluoro-2-methoxyphenyl)-1-(2-methoxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

5-Nitroquinoline-1-oxide

A solution of 25.5 g (146 mmol) of 5-nitroquinoline in 544 ml of aceticacid and 272 ml of 30% aqueous H₂O₂ solution are heated for 100 minutesto 62-69° C. The reaction mixture is poured onto saturated NaCl solutionand extracted with ethyl acetate. The combined extracts are concentratedby evaporation to about 50 ml with the addition of toluene. Columnchromatography on silica gel with ethyl acetate-MeOH yields 12.3 g ofthe product as a yellow solid.

H-NMR (CDCl₃): δ=7.5 (dd, 1H), 7.85 (t, 1H), 8.45 (d, 1H), 8.5 (d, 1H),8.6 (d, 1H), 9.15 (d, 1H).

2-Methoxy-5-nitroquinoline

A suspension of 1 g (5 mmol) of 5-nitroquinoline-1-oxide, 1.23 g (6.4mmol) of toluenesulfonic acid chloride and 1.4 ml (9.9 mmol) oftriethylamine in 30 ml of MeOH is stirred for 20 hours at roomtemperature. The solid is suctioned off and washed with MeOH: 565 mg oflight yellow product.

H-NMR (CDCl₃): δ=4.1 (s, 3H), 7.15 (d, 1H), 7.7 (t, 1H), 8.15 (d, 2H),8.8 (d, 1H).

5-Amino-2-methoxyquinoline

550 mg (2.7 mmol) of 2-methoxy-5-nitroquinoline is stirred in 15 ml ofethyl acetate in the presence of 138 mg of 10% Pd—C for 5 hours in ahydrogen atmosphere. The batch is filtered, and the filtrate isconcentrated by evaporation: 520 mg of a light yellow oil.

H-NMR (CDCl₃): δ=4.05 (s, 3H), 6.65 (d, 1H), 6.85 (d, 1H), 7.3 (d, 1H),7.4 (t, 1H), 8.0 (d, 1H).

4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

1.5 g (4.8 mmol) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-dioland 3.4 ml (24.4 mmol) of triethylamine in 17 ml of DMSO and 53 ml ofCH₂Cl₂ are mixed at 10° C. in portions with 3 g (18.9 mmol) ofpyridine-sulfur trioxide complex. After 3 hours at 12-18° C., it ishydrolyzed while being cooled with ice with saturated NH₄Cl solution,and it is extracted with ethyl acetate. The combined extracts are dried(Na₂SO₄) and concentrated by evaporation: 1.57 g of the product as alight yellow oil.

H-NMR (CDCl₃): δ=1.4 (s, 3H), 1.5 (s, 3H), 2.25 (d, 1H), 3.4 (d, 1H),3.6 (br., 1H), 3.85 (s, 3H), 6.8 (dd, 1H), 6.85-7.0 (m, 2H), 9.05 (s,1H).

4-(5-Fluoro-2-methoxyphenyl)-1-(2-methoxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

300 mg (0.97 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 202 mg (1.16 mmol) of 5-amino-2-methoxyquinoline in 10 ml of aceticacid are refluxed for 5 hours. It is allowed to cool to roomtemperature, 640 mg (3 mmol) of sodium triacetoxy borohydride is addedthereto, and it is stirred for 15 hours at room temperature. Aftertoluene is added, the batch is concentrated by evaporation, the residueis taken up in ethyl acetate, washed with saturated NaHCO₃ solution,dried and concentrated by evaporation. Column chromatography on silicagel with hexane-ethyl acetate yields 146 mg of the product as acolorless oil.

H-NMR (CDCl₃): δ=1.45 (s, 3H), 1.55 (s, 3H), 2.3 (d, 1H), 2.8 (d, 1H),3.1 (d, 1H), 3.2 (s, 1H), 3.3 (d, 1H), 3.85 (s, 3H), 4.05 (s, 3H), 5.95(m, 1H), 6.8 (m, 2H), 6.9 (td, 1H), 7.1 (dd, 1H), 7.35 (m, 2H), 7.85 (d,1H).

MS (ES): m/e=467.

Example 21

4-(5-Fluoro-2-hydroxyphenyl)-1-(2-methoxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

100 mg (0.21 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(2-methoxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olin 9 ml of CH₂Cl₂ is mixed at room temperature with 4 ml of 1M borontribromide-CH₂Cl₂ solution. After 15 hours at room temperature, thebatch is poured into saturated NaHCO₃ solution, stirred for 10 minutesand extracted with ethyl acetate. The combined organic extracts aredried (Na₂SO₄) and concentrated by evaporation in a vacuum.Chromatography on silica gel with hexane/ethyl acetate yields 73 mg ofthe product.

H-NMR (CDCl₃): δ=1.5 (s, 3H), 1.6 (s, 3H), 2.35 (d, 1H), 2.8 (d, 1H),3.2 (d, 1H), 3.3 (br., 1H), 3.4 (d, 1H), 4.05 (s, 3H), 6.0 (m, 1H), 6.7(dd, 1H), 6.8 (td, 1H), 6.85 (d, 1H), 7.1 (dd, 1H), 7.35 (m, 2H), 7.95(d, 1H).

MS (ES): m/e=453.

Example 22

1-(2-Ethoxyquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

2-Ethoxy-5-nitroquinoline

A suspension of 1 g (5 mmol) of 5-nitroquinoline-1-oxide, 1.23 g (6.4mmol) of toluenesulfonic acid chloride and 1.4 ml (9.9 mmol) oftriethylamine in 30 ml of EtOH is stirred for 60 hours at roomtemperature. The solid is suctioned off and washed with EtOH: 870 mg ofproduct.

H-NMR (CDCl₃): δ=1.45 (t, 3H), 4.55 (q, 2H), 7.1 (d, 1H), 7.65 (t, 1H),8.1 (d, 2H), 8.8 (d, 1H).

5-Amino-2-ethoxyquinoline

860 mg (3.9 mmol) of 2-ethoxy-5-nitroquinoline is stirred in 25 ml ofethyl acetate in the presence of 235 mg of 10% Pd—C for 4.5 hours in ahydrogen atmosphere. The batch is filtered, and the filtrate isconcentrated by evaporation: 720 mg of a light yellow oil.

H-NMR (CDCl₃): δ=1.45 (t, 3H), 4.5 (q, 2H), 6.65 (d, 1H), 6.85 (d, 1H),7.3 (d, 1H), 7.4 (t, 1H), 8.0 (d, 1H).

1-(2-Ethoxyquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 20, 500 mg (1.6 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 363 mg (1.9 mmol) of 5-amino-2-ethoxyquinoline are reacted to form338 mg of the product.

H-NMR (CDCl₃): δ=1.4 (t, 3H), 1.45 (s, 3H), 1.65 (s, 3H), 2.3 (d, 1H),2.8 (d, 1H), 3.1 (d, 1H), 3.2 (s, 1H), 3.3 (d, 1H), 3.85 (s, 3H), 4.55(q, 2H), 5.95 (m, 1H), 6.8 (m, 2H), 6.95 (td, 1H), 7.1 (dd, 1H), 7.35(m, 2H), 7.85 (d, 1H).

MS (ES): m/e=481.

Example 23

1-(2-Ethoxyquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 21, 200 mg (0.42 mmol) of1-(2-ethoxyquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olis converted into 172 mg of product.

H-NMR (CDCl₃): δ=1.45 (t, 3H), 1.5 (s, 3H), 1.6 (s, 3H), 2.35 (d, 1H),2.8 (d, 1H), 3.2 (d, 1H), 3.3 (br., 1H), 3.4 (d, 1H), 4.5 (q, 2H), 6.0(m, 1H), 6.7 (dd, 1H), 6.8 (m, 3H), 7.1 (dd, 1H), 7.35 (m, 2H), 7.95 (d,1H).

MS (ES): m/e=467.

Example 24

4-(5-Fluoro-2-methoxyphenyl)-1-(2-hydroxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol/4-(5-Fluoro-2-methoxyphenyl)-1-(2-quinolon-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

5-Amino-2-quinolone

1.45 g (8.3 mmol) of 5-amino-2-methoxyquinoline is refluxed in 29 ml of6N HCl for 4.5 hours. It is allowed to cool to room temperature, dilutedwith water, made basic with NaHCO₃, extracted with ethyl acetate, thecombined organic extracts are dried (Na₂SO₄) and concentrated byevaporation. Purification of the residue by chromatography on silica gelwith hexane-ethyl acetate yields 670 mg of a yellow solid.

H-NMR ([D]₆-DMSO): δ=5.85 (s, 2H), 6.25 (d, 1H), 6.35 (d, 1H), 6.45 (d,1H), 7.1 (t, 1H), 8.1 (d, 1H), 11.4 (br.s, 1H).

4-(5-Fluoro-2-methoxyphenyl)-1-(2-hydroxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol/4-(5-Fluoro-2-methoxyphenyl)-]-(2-quinolon-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 20, 226 mg (0.73 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 140 mg (0.87 mmol) of 5-amino-2-quinolone are reacted to form 200 mgof the product.

H-NMR ([D]₆-DMSO): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.05 (d, 1H), 2.8-3.05(m, 3H), 3.8 (s, 3H), 5.3 (m, 1H), 5.7 (d, 1H), 5.9 (s, 1H), 6.35 (d,1H), 6.55 (d, 1H), 6.9-7.15 (m, 3H), 7.85 (d, 1H), 11.5 (br.s, 1H).

MS (ES): m/e=453.

Example 25

4-(5-Fluoro-2-hydroxyphenyl)-1-(2-hydroxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol/4-(5-Fluoro-2-hydroxyphenyl)-1-(2-quinolon-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 21, 140 mg (0.31 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(2-hydroxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olis converted into 32 mg of product.

H-NMR ([D]₆-DMSO): δ=1.4 (s, 3H), 1.55 (s, 3H), 1.9 (d, 1H), 2.8-3.1 (m,3H), 5.25 (m, 1H), 5.65 (d, 1H), 5.9 (s, 1H), 6.35 (d, 1H), 6.55 (d,1H), 6.75 (dd, 1H), 6.85 (td, 1H), 7.0 (d, 1H), 7.1 (t, 1H), 7.85 (d,1H), 9.75 (br. s, 1H), 11.5 (br.s, 1H).

MS (ES): m/e=439.

Example 26

1-(2-Acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

2-Chloro-5-nitroquinoline

69 ml of 96% sulfuric acid is carefully added in drops to 84 ml of 100%nitric acid. While being cooled with ice, 25 g (152 mmol) of2-chloroquinoline is added thereto, and the batch is heated for 1 hourto 60° C. After cooling to room temperature, the batch is carefullyincorporated into an ice/water mixture. After 15 minutes of stirring,the solid is washed with water and dried in a vacuum at 40° C. Columnchromatography on silica gel with hexane-ethyl acetate yields 10.7 g ofa white solid.

H-NMR (CDCl₃): δ=7.65 (d, 1H), 7.85 (t, 1H), 8.35 (d, 1H), 8.4 (d, 1H),9.0 (d, 1H).

2-Amino-5-nitroquinoline

450 mg (2.2 mmol) of 2-chloro-5-nitroquinoline, 10 ml of 25% ammoniawater and 10 ml of THF are stirred in a pressure vessel for 8 hours at120° C. The batch is diluted with NaCl solution and extracted with ethylacetate. The combined organic phases are dried (Na₂SO₄) and concentratedby evaporation: 370 mg of product.

H-NMR ([D]₆-DMSO): δ=6.9 (br. s, 2H), 7.0 (d, 1H), 7.65 (t, 1H), 7.8 (d,1H), 7.9 (d, 1H), 8.35 (d, 1H).

2-Acetylamino-5-nitroquinoline

360 mg (1.9 mmol) of 2-amino-5-nitroquinoline is stirred with 4 ml (50mmol) of pyridine and 2 ml (21 mmol) of acetic anhydride for 15 hours atroom temperature. The batch is poured into saturated NaHCO₃ solution,stirred for 30 minutes, diluted with saturated NaCl solution andextracted with ethyl acetate. The extracts are dried (Na₂SO₄) andconcentrated by evaporation: 410 mg of a yellow solid.

H-NMR (CDCl₃): δ=2.3 (s, 3H), 7.75 (t, 1H), 8.1 (d, 1H), 8.2 (br. 1H),8.25 (d, 1H), 8.65 (d, 1H), 9.0 (d, 1H).

2-Acetylamino-5-aminoquinoline

400 mg (1.7 mmol) of 2-acetylamino-5-nitroquinoline and 105 mg of 10%Pd—C are stirred in 20 ml of ethyl acetate-MeOH (3:1) for 4 hours in ahydrogen atmosphere at room temperature. The batch is filtered,concentrated by evaporation and purified by column chromatography onsilica gel with hexane-ethyl acetate: 210 mg of product.

H-NMR ([D]₆-DMSO): δ=2.15 (s, 3H), 5.9 (s, 2H), 6.6 (d, 1H), 6.95 (d,1H), 7.35 (t, 1H), 8.1 (d, 1H), 8.5 (d, 1H).

1-(2-Acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 20, 263 mg (0.86 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 205 mg (1.0 mmol) of 2-acetylamino-5-aminoquinoline are reacted toform 197 mg of product.

H-NMR (CDCl₃): δ=1.45 (s, 3H), 1.55 (s, 3H), 2.25 (s, 3H), 2.3 (d, 1H),2.8 (d, 1H), 3.15 (dd, 1H), 3.2 (br., 1H), 3.3 (dd, 1H), 3.85 (s, 3H),4.3 (br., 3H), 5.95 (d, 1H), 6.8 (dd, 2H), 6.9 (td, 1H), 7.1 (dd, 1H),7.2 (d, 1H), 7.4 (t, 1H), 8.0 (d, 1H), 8.3 (m, 2H).

MS (ES): m/e=494.

Example 27

1-(2-Acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 21, 100 mg (0.20 mmol) of1-(2-acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olis converted into 79 mg of product.

H-NMR (CDCl₃): δ=1.5 (s, 3H), 1.6 (s, 3H), 2.2 (s, 3H), 2.35 (d, 1H),2.85 (d, 1H), 3.2 (dd, 1H), 3.35 (dd, 1H), 4.4 (br., 3H), 6.05 (d, 1H),6.6 (dd, 2H), 6.75 (td, 1H). 7.1 (dd, 1H), 7.15 (d, 1H), 7.4 (t, 1H),7.95 (d, 1H), 8.2 (d, 1H), 8.35 (br. 1H).

MS (ES): m/e=480.

Example 28

1-(2-Aminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

A solution of 535 mg (1.05 mmol) of1-(2-acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 18 ml of EtOH-THF (2:1) is refluxed with 12 ml of 3N sodium hydroxidesolution for 90 minutes. The batch is diluted with saturated NaCl andextracted with ethyl acetate. The extracts are dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. Column chromatography on silicagel with ethyl acetate yields 380 mg of the product as a yellow oil.

H-NMR ([D]₆-DMSO): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.05 (d, 1H), 2.7-3.0(m, 3H), 3.8 (s, 3H), 5.05 (m, 1H), 5.55 (d, 1H), 6.05 (br., 1H), 6.25(s, 2H), 6.6 (d, 1H), 6.75 (d, 1H), 6.9-7.2 (m, 3H), 7.85 (d, 1H).

MS (ES): m/e=452.

Example 29

1-(2-Aminoquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 28, 48 mg (0.1 mmol) of1-(2-acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olis converted into 21 mg of product.

H-NMR ([D]₆-DMSO): δ=1.4 (s, 3H), 1.55 (s, 3H), 1.95 (d, 1H), 2.85 (dd,1H), 3.05 (d, 1H), 5.05 (m, 1H), 5.6 (d, 1H), 6.25 (s, 2H), 6.6 (d, 1H),6.7 (m, 2H), 6.8 (m, 1H), 6.95 (dm, 1H), 7.1 (t, 1H), 7.85 (d, 1H).

MS (ES): m/e=438.

Example 30

1-(2-(Acetyl(methyl)amino)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

2-Methylamino-5-nitroquinoline

1.0 g (4.8 mmol) of 2-chloro-5-nitroquinoline and 20 ml of 2 Mmethanolic methylamine solution are heated in a pressure vessel for 8hours to 120° C. The batch is concentrated by evaporation after theaddition of toluene. The residue is purified by column chromatography onsilica gel with hexane-ethyl acetate: 580 mg of product.

H-NMR (CDCl₃): δ=3.1 (d, 3H), 4.95 (br., 1H), 6.8 (d, 1H), 7.55 (t, 1H),7.95 (2d, 2H), 8.6 (d, 1H).

2-Acetyl(methyl)amino-5-nitroquinoline

580 mg (2.4 mmol) of 2-methylamino-5-nitroquinoline is stirred with 4 ml(50 mmol) of pyridine and 2 ml (21 mmol) of acetic anhydride for 15hours at room temperature and stirred for 4.5 hours at 60° C. The batchis diluted with ethyl acetate, poured into saturated NaHCO₃ solution,stirred for 30 minutes, and extracted with ethyl acetate. The extractsare dried (Na₂SO₄) and concentrated by evaporation. The residue ispurified on silica gel with hexane-ethyl acetate: 660 mg of a yellowsolid.

H-NMR (CDCl₃): δ=2.35 (s, 3H), 3.6 (s, 3H), 7.75 (t, 1H), 7.9 (d, 1H),8.25 (d, 1H), 8.3 (d, 1H), 9.0 (d, 1H).

2-Acetyl(methyl)amino-5-aminoquinoline

650 mg (2.7 mmol) of 2-acetyl(methyl)amino-5-nitroquinoline and 161 mgof 10% Pd—C are stirred in 25 ml of ethyl acetate for 2 hours in ahydrogen atmosphere at room temperature. The batch is filtered andconcentrated by evaporation: 490 mg of product.

H-NMR (CDCl₃): δ=2.2 (s, 3H), 3.5 (s, 3H), 4.2 (br., 2H), 6.8 (d, 1H),7.4 (d, 1H), 7.45 (d, 1H), 7.5 (t, 1H), 8.2 (d, 1H).

1-(2-(Acetyl(methyl)amino)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 20, 576 mg (1.9 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 480 mg (2.2 mmol) of 2-acetyl(methyl)amino-5-aminoquinoline arereacted to form 330 mg of product.

H-NMR (CDCl₃): δ=1.45 (s, 3H), 1.55 (s, 3H), 2.2 (s, 3H), 2.4 (d, 1H),2.75 (d, 1H), 3.15 (dd, 1H), 3.2 (s, 1H), 3.35 (dd, 1H), 3.5 (s, 3H),3.85 (s, 3H), 4.3 (m, 1H), 6.1 (d, 1H), 6.8 (dd, 1H), 6.95 (td, 1H), 7.1(dd, 1H), 7.3-7.5 (m, 3H), 8.0 (d, 1H).

MS (ES): m/e=508.

Example 31

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-(methylamino)quinolin-5-ylamino)-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 28, 83 mg (0.16 mmol) of1-(2-(acetyl(methyl)amino)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olis converted into 48 mg of product.

H-NMR (CDCl₃): δ=1.4 (t, 3H), 1.5 (s, 3H), 2.2 (d, 1H), 2.75 (d, 1H),2.95 (d, 3H), 3.0 (m, 1H), 3.2 (m, 1H), 3.8 (s, 3H), 4.0 (m, 1H), 5.05(br., 1H), 5.75 (d, 1H), 6.5 (d, 2H), 6.75 (dd, 1H), 6.9 (td, 1H), 7.05(dd, 1H), 7.1 (m, 1H), 7.2 (m, 1H), 7.65 (d, 1H).

MS (ES): m/e=466.

Example 32

1-(2-(Acetyl(methyl-amino)-6,8-dibromoquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

200 mg (0.39 mmol) of1-(2-(acetyl(methyl)amino)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 17 ml of CH₂Cl₂ is mixed at 0° C. with 7.6 ml of 1M borontribromide-CH₂Cl₂ solution. After 15 hours at room temperature, 7.6 mlof 1M boron tribromide-CH₂Cl₂ solution is added once more and stirredfor 20 hours at room temperature. The batch is poured into saturatedNaHCO₃ solution, diluted with NaCl solution and ethyl acetate, stirredfor 15 minutes and extracted with ethyl acetate. The combined organicextracts are dried (Na₂SO₄) and concentrated by evaporation.Chromatography with hexane-ethyl acetate on silica gel yields 98 mg ofthe product.

H-NMR (CDCl₃): δ=1.4 (t, 3H), 1.55 (s, 3H), 2.3 (d, 1H), 2.45 (s, 3H),2.6 (d, 1H), 2.95 (t, 1H), 3.25 (dd, 1H), 3.65 (s, 3H), 3.95 (s, 1H),4.1 (m, 1H), 5.7 (br. s, 1H), 6.45 (dd, 1H), 6.6 (td, 1H), 6.9 (dd, 1H),7.6 (d, 1H), 7.95 (d, 1H), 8.05 (s, 1H).

MS (ES): m/e=650, 652, 654 (1:2:1).

Example 33

1-(6,8-Dibromo-2-(methylamino)quinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 28, 100 mg (0.15 mmol) of1-(2-(acetyl(methyl)amino)-6,8-dibromoquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olis converted into 97 mg of product.

H-NMR ([D]₆-DMSO): δ=1.3 (s, 3H), 1.5 (s, 3H), 1.95 (d, 1H), 2.95 (d,3H), 3.0 (d, 1H), 3.15 (dd, 1H), 4.4 (m, 1H), 6.15 (s, 1H), 6.65 (m,2H), 6.75 (td, 1H), 6.85 (dd, 1H), 7.35 d, 1H), 7.55 (d, 1H), 7.8 (s,1H), 9.55 (s, 1H).

Example 34

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-(methylamino)quinolin-5-ylamino)-2-(trifluoromethyl)pentan-2-ol

45 mg (0.07 mmol) of1-(6,8-dibromo-2-(methylamino)quinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-oland 50 mg of 10% Pd—C are stirred in 2 ml for 90 minutes under hydrogenatmosphere. The batch is filtered and concentrated by evaporation.Column chromatography on silica gel with ethyl acetate-MeOH yields 19 mgof the product.

H-NMR ([D]₆-DMSO): δ=1.4 (s, 3H), 1.55 (s, 3H), 1.9 (d, 1H), 2.8 (d, 3Hund m, 1H), 3.05 (d, 1H), 3.15 (d, 1H), 4.95 (m, 1H), 5.6 (d, 1H), 5.95(s, 1H), 6.6 (d, 1H), 6.75 (dd, 1H), 6.8 (d, 1H), 6.85 (td, 1H), 7.0(dd, 1H), 7.05 (t, 1H), 7.8 (d, 1H), 9.7 (s, 1H).

MS (ES): m/e=452.

Example 35

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)pentan-2-ol

300 mg (0.97 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 184 mg (1.16 mmol) of 5-amino-2-methylquinoline are heated in 10 mlof acetic acid over 6 hours to 125° C. After cooling to roomtemperature, it is mixed with 320 mg (1.51 mmol) of sodium triacetoxyborohydride, and it is allowed to stir for 16 hours. After the additionof another 320 mg (1.51 mmol) of sodium triacetoxy borohydride and 2hours of stirring, toluene is added, and it is concentrated byevaporation in a vacuum. The residue is taken up in ethyl acetate, theorganic phase is washed with saturated sodium bicarbonate and saturatedsodium chloride solution, and it is dried on sodium sulfate. Afterchromatography on silica gel with hexane-ethyl acetate (0-60%), 221 mgof the product is obtained.

¹H-NMR (CDCl₃); δ=1.46 (s, 3H), 1.57 (s, 3H), 2.33 (d, 1H), 2.72 (s,3H), 2.78 (d, 1H), 3.12 (dd, 1H), 3.30 (dd, 1H), 3.84 (s, 3H), 4.23(br., 1H), 6.01 (d, 1H), 6.80 (dd, 1H), 6.94 (ddd, 1H), 7.12 (dd, 1H),7.21 (d, 1H), 7.41 (t, 1H), 7.46 (d, 1H), 7.88 (d, 1H).

Example 36

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogously to Example 35, 153 mg (0.34 mmol) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-olin 17 ml of CH₂Cl₂ is reacted with 6.8 ml of 1M boron tribromide-CH₂Cl₂solution. After chromatography on silica gel with hexane-ethyl acetate(0-55%), 99 mg of the product is obtained.

¹H-NMR (CDCl₃); δ=1.51 (s, 3H), 1.59 (s, 3H), 2.41 (d, 1H), 2.70 (s,3H), 2.80 (d, 1H), 3.24 (dd, 1H), 3.42 (dd, 1H), 4.32 (br, 1H), 6.06 (d,1H), 6.63 (dd, 1H), 6.80 (ddd, 1H), 7.09 (dd, 1H), 7.18 (d, 1H), 7.35(t, 1H), 7.42 (d, 1H), 7.87 (d, 1H).

Example 37

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide

5-Aminoquinoline-2-carboxylic acid amide

840 mg (4.16 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester isdissolved in 70 ml of a 7N methanolic ammonia solution. It is stirredfor 3.5 hours at 40° C., then for 20 hours at room temperature. Afterthe solvent is removed in a vacuum, the purification is carried out onsilica gel with hexane-ethyl acetate (0-100%) as well as with ethylacetate-methanol (0-10%). 690 mg (88% of theory) of the product isobtained.

¹H-NMR (DMSO-d₆): δ=6.11 (s, 2H), 6.78 (d, 1H), 7.27 (d, 1H), 7.51 (t,1H), 7.70 (s, 1H), 7.96 (d, 1H), 8.20 (s, 1H), 8.68 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-quinoline-2-carboxylicacid amide

A solution that consists of 290 mg (1.55 mmol) of5-aminoquinoline-2-carboxylic acid amide, 616 mg (2.0 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanaland 3.80 ml of concentrated acetic acid in 30 ml of toluene is refluxedfor 20 hours in a water separator. Then, the solvent is removed in avacuum. After the residue is purified on silica gel with hexane/ethylacetate (0-70%), 438 mg (59% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.33 (s, 3H), 1.53 (s, 3H), 2.20 (d, 1H),3.33 (d, 1H), 3.77 (s, 3H), 6.31 (s, 1H), 6.48-6.55 (m, 1H), 6.70-6.75(m, 3H), 7.59 (s, 1H), 7.70 (t, 1H), 7.82 (br, 1H), 7.98 (d, 1H), 8.31(br, 1H), 8.82 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide

253 mg (0.53 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]quinoline-2-carboxylicacid amide is dissolved in 10 ml of tetrahydrofuran-methanol (50%) andmixed with 101 mg (2.65 mmol) of sodium borohydride. After 20 hours, thesolvent is removed in a vacuum. The subsequent recrystallization of theresidue from ethyl acetate-methanol and purification of the motherliquor that is concentrated by evaporation on silica gel withhexane-ethyl acetate (0-50%) yield 116 mg (46% of theory) of theproduct.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.38 (s, 3H), 1.56 (s, 3H), 2.05 (d, 1H),2.91-2.96 (m, 2H), 3.07 (d, 1H), 3.78 (s, 3H), 5.59 (t, 1H), 5.99 (s,1H), 6.02 (d, 1H), 6.91-7.06 (m, 2H), 7.08 (dd, 1H), 7.32 (d, 1H), 7.46(t, 1H), 7.72 (br, 1H), 8.03 (d, 1H), 8.21 (br, 1H), 8.49 (d, 1H).

Example 38

5-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide

220 mg (0.46 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide is dissolved in 5.0 ml of dichloromethane and mixed with 9.2ml of a 1N boron tribromide solution in dichloromethane. After 20 hoursat room temperature, the reaction is halted by adding methanol. Thesolvent is removed in a vacuum, the residue is taken up in saturatedsodium bicarbonate solution and ethyl acetate, extracted with ethylacetate, and the combined organic phases are dried on sodium sulfate.After removal of the solvent and purification on silica gel withhexane-ethyl acetate (0-100%), 60 mg (28% of theory) of the product isobtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.40 (s, 3H), 1.57 (s, 3H), 1.93 (d, 1H),2.98 (dd, 1H), 3.16-3.20 (m, 2H), 5.52 (br, 1H), 5.99 (br, 1H), 6.68(dd, 1H), 6.78-6.84 (m, 1H), 7.01 (dd, 1H), 7.32 (d, 1H), 7.45 (t, 1H),7.71 (s, 1H), 8.03 (d, 1H), 8.21 (s, 1H), 8.46 (d, 1H), 9.73 (s, 1H).

Example 39

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid nitrile

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]-quinoline-2-carboxylicacid nitrile

220 mg (0.46 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]quinoline-2-carboxylicacid amide and 1.80 ml (3.2 mmol) of triethylamine are dissolved in 18ml of dichloromethane and mixed with 0.44 ml (1.38 mmol) oftrifluoroacetic acid anhydride. After 2 minutes, the reaction is haltedby adding water. It is extracted three times with ethyl acetate, and thecombined organic phases are washed with a 1N sodium hydroxide solution.After drying on sodium sulfate, removal of the solvent in a vacuum aswell as chromatography on silica gel with hexane-ethyl acetate (0-100%),190 mg (90% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.57 (s, 3H), 2.30 (d, 1H),3.47 (d, 1H), 3.80 (s, 3H), 4.69 (s, 1H), 6.38-6.43 (m, 1H), 6.59-6.60(m, 2H), 6.80 (dd, 1H), 7.54 (s, 1H), 7.65 (t, 1H), 7.74 (d, 1H), 8.03(d, 1H), 8.44 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid nitrile

Analogously to Example 37, 90 mg (0.2 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]-quinoline-2-carboxylicacid nitrile is reacted with 31 mg (0.8 mmol) of sodium in 5.0 ml ofmethanol and 1.0 ml of tetrahydrofuran. After working-up andchromatography on silica gel with hexane-ethyl acetate (0-100%), 50 mg(54% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.38 (s, 3H), 1.56 (s, 3H), 2.05 (d, 1H),2.88-3.11 (m, 3H), 3.78 (s, 3H), 5.82-5.84 (m, 1H), 5.94 (s, 1H), 6.14(d, 1H), 6.89-7.09 (m, 3H), 7.31 (d, 1H), 7.54 (t, 1H), 7.93 (d, 1H),8.61 (d, 1H).

Example 40

8-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide

8-Aminoquinoline-2-carboxylic acid amide

Analogously to Example 37, 120 mg (0.59 mmol) of8-aminoquinoline-2-carboxylic acid methyl ester is reacted with 10 ml ofa 7N methanolic ammonia solution. After purification on silica gel withhexane-ethyl acetate, 79 mg (72% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=6.51 (br, 2H), 6.84 (d, 1H), 7.04 (d, 1H),7.35 (t, 1H), 7.58 (br, 1H), 8.03 (d, 1H), 8.27 (d, 1H), 8.87 (br, 1H).

8-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]-quinoline-2-carboxylicacid amide

Analogously to Example 37, 535 mg (2.86 mmol) of a mixture that consistsof 5- and 8-aminoquinoline-2-carboxylic acid amide is reacted with 1.06g (3.43 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalin 4.50 ml of concentrated acetic acid and 20 ml of toluene. After 40hours, the purification on silica gel with hexane-ethyl acetate (0-40%)takes place, and 624 mg (46% of theory) of the desired product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.60 (s, 3H), 2.27 (d, 1H),3.46 (d, 1H), 3.70 (s, 3H), 5.08 (s, 1H), 5.60 (br, 1H), 6.34-6.48 (m,2H), 6.83 (dd, 1H), 7.00 (d, 1H), 7.49-7.59 (m, 2H), 7.65-7.78 (m, 2H),8.32 (s, 2H).

8-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide

703 mg (1.47 mmol) of8-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]quinoline-2-carboxylicacid amide in 10 ml of methanol and 5.0 ml of tetrahydrofuran are mixedwith 449 mg (11.8 mmol) of sodium borohydride. After 16 hours, thesolvent is concentrated by evaporation, the residue is taken up in waterand ethyl acetate, extracted with ethyl acetate, and the combinedorganic phases are dried on sodium sulfate. After removal of the solventand purification on silica gel with hexane-ethyl acetate (0-50%) as wellas dichloromethane-methanol (0-7%), 358 mg (51% of theory) of theproduct is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.39 (s, 3H), 1.58 (s, 3H), 2.10 (d, 1H),2.86 (d, 1H), 3.13 (d, 2H), 3.76 (s, 3H), 5.87 (s, 1H), 6.24 (d, 1H),6.81-6.97 (m, 3H), 7.06-7.11 (m, 2H), 7.32 (t, 1H), 7.76 (br, 1H), 8.06(d, 1H), 8.31 (d, 1H), 8.45 (br, 1H).

Example 41

8-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid nitrile

185 mg (0.386 mmol) of8-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]quinoline-2-carboxylicacid amide in 5.0 ml of dimethylformamide is mixed with 397 mg (2.80mmol) of diphosphorus pentoxide. After five days at room temperature,insoluble components are filtered off. The filtrate is diluted withethyl acetate and saturated sodium chloride solution. It is extractedwith ethyl acetate, the combined organic phases are dried on sodiumsulfate, and then the solution is concentrated by evaporation.Dimethylformamide radicals are removed under high vacuum. Afterpurification on silica gel with hexane-ethyl acetate (0-30%), 102 mg(57% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.37 (s, 3H), 1.56 (s, 3H), 1.99 (d, 1H),2.95 (dd, 1H), 3.03 (d, 1H), 3.13 (dd, 1H), 3.79 (s, 3H), 6.16-6.17 (m,2H), 6.23 (d, 1H), 6.76-6.79 (m, 2H), 7.01 (dd, 1H), 7.15 (d, 1H), 7.43(t, 1H), 7.96 (d, 1H), 8.44 (d, 1H).

Example 42

1-(2-Ethylquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

2-Chloro-5-nitroquinoline

10.0 g (61.1 mmol) of 2-chloroquinoline is dissolved in 34 ml ofconcentrated sulfuric acid. At 0° C., 8.4 g (76.4 mmol) of potassiumnitrate is added in portions. After 20 hours at room temperature, thereaction mixture is poured onto ice water, and the aqueous phase isextracted with ethyl acetate. The combined organic phases are washedwith saturated sodium bicarbonate solution and dried on sodium sulfate.After the solvent is removed in a vacuum and after chromatography onsilica gel with hexane-ethyl acetate (10-100%), 5.06 g (40% of theory)of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=7.62 (d, 1H), 7.84 (t, 1H), 8.33 (d, 1H),8.39 (d, 1H), 8.98 (d, 1H).

5-Nitro-2-vinylquinoline

5.06 g (24.5 mmol) of 2-chloro-5-nitroquinoline, 1.26 g (4.9 mmol) oftriphenylphosphine and 8.0 g (25.2 mmol) of tri-n-butylvinyltin aredissolved in 60 ml of toluene. After adding 2.75 g (2.5 mmol) oftris(dibenzylidenacetone)dipalladium, the reaction mixture is allowed toreflux for 20 hours. Then, it is filtered on Celite and washed withethyl acetate. The filtrate is mixed with saturated ammonium chloridesolution. It is extracted with ethyl acetate, and the combined organicphases are dried on sodium sulfate. After the solvent is removed in avacuum and after subsequent chromatography on silica gel withhexane-ethyl acetate (5-20%), 3.05 g (62% of theory) of the product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=5.78 (d, 1H), 6.40 (d, 1H), 7.03 (dd, 1H),7.75-7.81 (m, 2H), 8.28-8.38 (m, 2H), 8.95 (d, 1H).

2-Ethylquinolin-5-ylamine

1.0 g (5.0 mmol) of 5-nitro-2-vinylquinoline is dissolved in 30 ml ofethyl acetate. After 100 mg of palladium on carbon and 50 mg of sodiumcarbonate are added, the reaction mixture is allowed to stir for 20hours at room temperature under hydrogen atmosphere. It is then filteredon Celite and washed with ethyl acetate. After the solvent is removed ina vacuum and after chromatography on silica gel with hexane-ethylacetate (0-100%), then with ethyl acetate-methanol (0-30%), 720 mg (84%of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.29 (t, 3H), 2.86 (q, 2H), 5.87 (br, 2H),6.63 (d, 1H), 7.09 (d, 1H), 7.25 (d, 1H), 7.35 (t, 1H), 8.41 (d, 1H).

1-(2-Ethylquinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 37, 334 mg (1.94 mmol) of2-ethylquinolin-5-ylamine is reacted with 500 mg (1.62 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanalin 2.20 ml of concentrated acetic acid and 15 ml of toluene. Afterpurification on silica gel with hexane-ethyl acetate (0-100%), 600 mg(80% of theory) of the corresponding imine is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (s, 3H), 1.41 (t, 3H), 1.57 (s, 3H),2.30 (d, 1H), 3.03 (q, 2H), 3.42 (d, 1H), 3.80 (s, 3H), 4.88 (s, 1H),6.40-6.56 (m, 3H), 6.81 (dd, 1H), 7.37 (d, 1H), 7.47-7.55 (m, 2H), 7.92(d, 1H), 8.20 (d, 1H).

1-(2-Ethylquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

600 mg (1.3 mmol) of1-(2-ethylquinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 5.0 ml of methanol is mixed at 0° C. with 197 mg (5.2 mmol) of sodiumborohydride. After 2 hours at room temperature, water is added, andmethanol is removed in a vacuum. The aqueous phase is extracted withdichloromethane, the combined organic phases are dried on sodiumsulfate, and the solvent is removed in a vacuum. After purification onsilica gel with hexane-ethyl acetate (0-100%), 400 mg (66% of theory) ofthe product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (t, 3H), 1.46 (s, 3H), 1.57 (s, 3H),2.33 (d, 1H), 2.78 (d, 1H), 2.98 (q, 2H), 3.13 (dd, 1H), 3.19 (br, 1H),3.30 (dd, 1H), 3.84 (s, 3H), 4.24 (br, 1H), 6.01 (d, 1H), 6.80 (dd, 1H),6.91-6.98 (m, 1H), 7.12 (dd, 1H), 7.23 (d, 1H), 7.38-7.49 (m, 2H), 7.91(d, 1H).

Example 43

1-(2-Ethylquinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

230 mg (0.49 mmol) of1-(2-ethylquinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 4.5 ml of dichloromethane is mixed at 0° C. with 7.30 ml (7.30 mmol)of a 1 M boron tribromide solution. After 23 hours at room temperature,the reaction is brought to a halt by the addition of 30 ml of methanol.The reaction mixture is allowed to stir for one hour at roomtemperature, and then the solvent is removed in a vacuum. Afterchromatography on silica gel with ethyl acetate-methanol (0-10%), 60 mg(27% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.29 (t, 3H), 1.40 (s, 3H), 1.56 (s, 3H),1.93 (d, 1H), 2.87 (q, 2H), 2.95 (d, 1H), 3.08-3.20 (m, 2H), 5.34 (br,1H), 5.89 (d, 1H), 5.96 (s, 1H), 6.73 (dd, 1H), 6.83-6.88 (m, 1H), 7.01(dd, 1H), 7.14 (d, 1H), 7.27-7.34 (m, 2H), 8.18 (d, 1H), 9.73 (s, 1H).

Example 44

1-(Quinolin-5-ylamino)-3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-ol

1-(Quinolin-5-ylimino)-3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-ol

Analogously to Example 37, 362 mg (2.5 mmol) of 5-aminoquinoline isreacted with 640 mg (2.09 mmol) of3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanaland 2.80 ml of concentrated acetic acid in 19 ml of toluene. After 6hours, the chromatography is carried out on silica gel with hexane-ethylacetate (0-100%), and 810 mg (90% of theory) of the product is obtained.

MS (ES+): m/z (r.I. %)=433 (M+1, 100).

1-(Quinolin-5-ylamino)-3-[1-(S-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-ol

810 mg (1.87 mmol) of1-(quinolin-5-ylimino)-3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-olis reacted with 288 mg (7.61 mmol) of sodium borohydride in 6.0 ml ofmethanol and 3.0 ml of tetrahydrofuran as in Example 1. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 660 mg(81% of theory) of the product is obtained.

¹H-NMR (400 MHz, CDCl₃): δ=0.85-0.99 (m, 4H), 2.19 (d, 1H), 2.32 (d,1H), 3.19-3.29 (m, 2H), 3.70 (s, 3H), 3.83 (s, 1H), 4.47 (t, 1H), 6.31(d, 1H), 6.61 (dd, 1H), 6.84 (ddd, 1H), 7.06 (dd, 1H), 7.33 (dd, 1H),7.46-7.52 (m, 2H), 8.05 (d, 1H), 8.87 (dd, 1H).

Example 45

1-(Quinolin-5-ylamino)-3-[1-(5-fluoro-2-hydroxyphenl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-ol

Analogously to Example 38, 330 mg (0.76 mmol) of1-(quinolin-5-ylamino)-3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-olis reacted with 3.80 ml (3.80 mmol) of a 1 M boron tribromide solutionin 6.90 ml of dichloromethane. After 2 hours, the reaction is halted.The recrystallization from ethyl acetate and methanol yields 292 mg (91%of theory) of the product.

¹H-NMR (400 MHz, DMSO-d₆): δ=0.63-0.65 (m, 1H), 0.79-0.84 (m, 3H), 1.97(d, 1H), 2.62 (d, 1H), 3.35 (m, 2H), 5.93 (br, 1H), 6.26 (br, 1H), 6.42(dd, 1H), 6.51 (d, 1H), 6.64 (td, 1H), 6.91 (dd, 1H), 7.31 (d, 1H), 7.71(t, 1H), 7.83 (dd, 1H), 9.08-9.12 (m, 2H), 9.34 (s, 1H).

Example 46

3-[1-(5-Fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol

3-[1-(5-Fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylimino)-2-(trifluoromethyl)propan-2-ol

Analogously to Example 1, 352 mg (2.23 mmol) of5-amino-2-methylquinoline is reacted with 650 mg (2.12 mmol) of3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanaland 2.80 ml of concentrated acetic acid in 19 ml of toluene. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 870 mg(92% of theory) of the product is obtained.

MS (ES+): m/z (r.I. %)=447 (M+1, 100).

3-[1-(5-Fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol

870 mg (1.95 mmol) of3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylimino)-2-(trifluoromethyl)propan-2-olis reacted analogously to Example 37 with 96 mg (2.53 mmol) of sodiumborohydride in 6.0 ml of methanol and 3.0 ml of tetrahydrofuran. Afterrecrystallization from hexane and ethyl acetate, 790 mg (90% of theory)of the product is obtained.

¹H-NMR (400 MHz, CDCl₃): δ=0.83-0.97 (m, 4H), 2.19 (d, 1H), 2.31 (d,1H), 2.72 (s, 3H), 3.21-3.25 (m, 2H), 3.70 (s, 3H), 3.79 (s, 1H), 4.41(t, 1H), 6.25 (dd, 1H), 6.61 (dd, 1H), 6.86 (ddd, 1H), 7.05 (dd, 1H),7.21 (d, 1H), 7.43-7.44 (m, 2H), 7.94 (d, 1H).

Example 47

3-[1-(5-Fluoro-2-hydroxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol

Analogously to Example 38, 395 mg (0.88 mmol) of3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)propan-2-olis reacted with 4.30 ml (4.3 mmol) of a 1 M boron tribromide solution in8.0 ml of dichloromethane. After one hour at 0° C., the reaction ishalted. The subsequent recrystallization from ethyl acetate, acetone andmethanol yields 257 mg (67% of theory) of the product.

MS (ES+): m/z (r.I.%)=435 (M+1, 100).

Example 48

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylamino)pentan-2-ol

2-(Trifluoromethyl)quinoline

According to instructions in the literature (Baraznenok, I. L.,Nenajdenko, V. G., Balenkova, E. S. Eur. J. Org. Chem. 1999, 937-941),1.2 g (7.18 mmol) of(E)-4-(dimethylamino)-1,1,1-trifluoro-3-buten-2-oneis reacted with 2.03 g (7.18 mmol) of trifluoroacetic acid anhydride and1.30 ml (14.36 mmol) of aniline in 72 ml of 1,2-dichloroethane, then in36 ml of xylene. After working-up and purification on silica gel withhexane-ethyl acetate (0-100%), 1.01 g (71% of theory) of the product isobtained.

5-Nitro-2-(trifluoromethyl)quinoline

1.52 g (7.7 mmol) of 2-(trifluoromethyl)quinoline is dissolved in 7.90ml of concentrated sulfuric acid, and 1.47 g of potassium nitrate isadded in portions at 0° C. After 20 hours at room temperature, thereaction solution is poured onto ice/water. It is extracted with ethylacetate, the combined organic phases are washed with saturated sodiumbicarbonate solution and dried on sodium sulfate. After removal of thesolvent and chromatography on silica gel with hexane-ethyl acetate(10-100%), 390 mg (21% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=7.92-8.00 (m, 2H), 8.53-8.58 (m, 2H), 9.26(d, 1H).

5-Amino-2-(trifluoromethyl)quinoline

390 mg (1.61 mmol) of 5-nitro-2-(trifluoromethyl)quinoline is dissolvedin 13 ml of methanol. After the addition of 39 mg of palladium on carbonand 19 mg of potassium carbonate, the reaction mixture is allowed tostir for 20 hours at room temperature under hydrogen atmosphere. It isthen filtered on Celite and washed with ethyl acetate. After the solventis removed in a vacuum and after chromatography on silica gel withhexane-ethyl acetate (0-100%), 250 mg (73% of theory) of the product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=4.28 (br, 2H), 6.92 (d, 1H), 7.58-7.69 (m,3H), 8.36 (d, 1H).

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylimino)pentan-2-ol

Analogously to Example 37, 250 mg (1.18 mmol) of5-amino-2-(trifluoromethyl)quinoline is reacted with 438 mg (1.42 mmol)of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 1.30 ml of concentrated acetic acid in 20 ml of toluene. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 500 mg(84% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (s, 3H), 1.58 (s, 3H), 2.31 (d, 1H),3.47 (d, 1H), 3.80 (s, 3H), 4.75 (s, 1H), 6.39-6.45 (m, 1H), 6.51-6.58(m, 2H), 6.82 (dd, 1H), 7.55 (s, 1H), 7.64 (t, 1H), 7.78 (d, 1H), 8.10(d, 1H), 8.49 (d, 1H).

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)-quinolin-5-ylamino)pentan-2-ol

Analogously to Example 37, 500 mg (0.99 mmol) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylimino)-pentan-2-olis reacted with 154 mg (4.04 mmol) of sodium borohydride in 5.0 ml ofmethanol. After purification on silica gel with hexane-ethyl acetate(0-100%), 420 mg (84% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.47 (s, 3H), 1.55 (s, 3H), 2.42 (d, 1H),2.74 (d, 1H), 3.03 (s, 1H), 3.16 (dd, 1H), 3.34 (dd, 1H), 3.85 (s, 3H),4.38 (dd, 1H), 6.20 (d, 1H), 6.79 (dd, 1H), 6.91-6.97 (m, 1H), 7.10 (dd,1H), 7.52-7.65 (m, 3H), 8.14 (d, 1H).

Example 49

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)-quinolin-5-ylamino)pentan-2-ol

100 mg (0.20 mmol) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylamino)pentan-2-olin 2.0 ml of dichloromethane is mixed at room temperature with 4.0 ml(4.0 mmol) of a 1 M boron tribromide solution. After 20 hours at roomtemperature, the reaction is brought to a halt by adding 20 ml ofmethanol. The reaction mixture is allowed to stir for 30 minutes at roomtemperature, and then the solvent is removed in a vacuum. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 79 mg(80% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.51 (s, 3H), 1.57 (s, 3H), 2.45 (d, 1H),2.76 (d, 1H), 3.21-3.27 (m, 2H), 3.42 (dd, 1H), 4.43 (br, 1H), 5.60 (br,1H), 6.23 (d, 1H), 6.59 (dd, 1H), 6.75-6.87 (m, 1H), 7.07 (dd, 1H),7.51-7.65 (m, 3H), 8.14 (d, 1H).

Example 50

1-(2-(Acetoxymethyl)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

1-(1,2-Dihydroxyethyl)-5-nitroquinoline

336 mg (2.5 mmol) of N-methylmorpholine-N-oxide hydrate and 10.22 ml ofosmium tetroxide solution in isopropanol are added at 0° C. to asolution that consists of 3.18 g (15.88 mmol) of5-nitro-2-vinylquinoline in 140 ml of acetone and 21 ml of water, andthe reaction mixture is stirred for 24 hours at room temperature. Then,the solvent is removed in a vacuum, and the residue is taken up in ethylacetate. The organic phase is washed with water and saturated sodiumchloride solution. The aqueous phase is extracted repeatedly withdichloromethane, diethyl ether and ethyl acetate. The combined organicphases are dried on sodium sulfate. After removal of the solvent andpurification of silica gel with hexane-ethyl acetate (0-100%) as well aswith ethyl acetate-methanol (0-20%), 1.64 g (44% of theory) of theproduct is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=3.62-3.81 (m, 2H), 4.78-4.84 (m, 2H), 5.76(d, 1H), 7.90-7.96 (m, 2H), 8.37-8.42 (m, 2H), 8.83 (d, 1H).

5-Nitroquinoline-2-carbaldehyde

2.99 g (14.0 mmol) of sodium periodate is added to a solution thatconsists of 1.64 g (7.0 mmol) of 1-(1,2-dihydroxyethyl)-5-nitroquinolinein 42 ml of tetrahydrofuran and 7.0 ml of water. After 20 hours at roomtemperature, ethyl acetate is added, and the organic phase is washedwith saturated sodium chloride solution. After the organic phase isdried on sodium sulfate, after the solvent is removed, and afterpurification on silica gel with hexane-ethyl acetate (0-100%), 1.40 g(99% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=7.94 (t, 1H), 8.24 (d, 1H), 8.53 (d, 1H),8.58 (d, 1H), 9.18 (d, 1H), 10.24 (s, 1H).

2-(Hydroxymethyl)-5-nitroquinoline

700 mg (3.46 mmol) of 5-nitroquinoline-2-carbaldehyde are dissolved in13 ml of methanol and 7.0 ml of tetrahydrofuran and mixed at 0° C. with523 mg (13.9 mmol) of sodium borohydride. After 5 hours, the reaction isbrought to a halt by adding water. The solvent is removed in a vacuum,the residue is taken up in dichloromethane and water, the aqueous phaseis extracted with dichloromethane, and the combined organic phases aredried on sodium sulfate. After the solvent is removed, and afterpurification on silica gel with hexane-ethyl acetate (0-100%), 390 mg(55% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=4.13 (br, 1H), 4.99 (s, 2H), 7.55 (d, 1H),7.82 (t, 1H), 8.36-8.41 (m, 2H), 8.99 (d, 1H).

2-(Acetoxymethyl)-5-nitroquinoline

A solution that consists of 390 mg (1.91 mmol) of2-(hydroxymethyl)-5-nitroquinoline and 2.5 ml of acetic acid anhydridein 5.0 ml of pyridine is allowed to stir for 24 hours at roomtemperature. After repeated co-evaporation with toluene and subsequentchromatography on silica gel with hexane-ethyl acetate (0-100%), 410 mg(87% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.23 (s, 3H), 5.42 (s, 2H), 7.70 (d, 1H),7.81 (t, 1H), 8.37-8.40 (m, 2H), 9.02 (d, 1H).

2-(Acetoxymethyl)-5-aminoquinoline

Under hydrogen atmosphere, a solution that consists of 410 mg (1.67 mol)of 2-(acetoxymethyl)-5-nitroquinoline in 61 ml of acetone can be stirredin the presence of 410 mg of Raney nickel for 2 hours at roomtemperature. It is suctioned off on Celite and rewashed with acetone.After removal of the solvent and subsequent chromatography on silica gelwith hexane-ethyl acetate (10-100%), 230 mg (64% of theory) of theproduct is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.19 (s, 3H), 4.20 (br, 2H), 5.37 (s, 2H),6.81 (dd, 1H), 7.41 (d, 1H), 7.51-7.53 (m, 2H), 8.19 (d, 1H).

1-(2-(Acetoxymethyl)quinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 37, 230 mg (1.06 mmol) of2-(acetoxymethyl)-5-aminoquinoline is reacted with 273 mg (0.88 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 1.20 ml of concentrated acetic acid in 20.0 ml of toluene. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 360 mg(81% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.57 (s, 3H), 2.21 (s, 3H),2.32 (d, 1H), 3.44 (d, 1H), 3.79 (s, 3H), 4.84 (s, 1H), 5.40 (s, 2H),6.42-6.56 (m, 3H), 6.82 (dd, 1H), 7.45-7.60 (m, 3H), 7.95 (d, 1H), 8.31(d, 1H).

1-(2-(Acetoxymethyl)quinolin-5-ylamino)-4-(S-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

A solution that consists of 170 mg (0.34 mmol) of1-(2-(acetoxymethyl)quinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olin 1.5 ml of methanol and 0.8 ml of tetrahydrofuran is mixed with 53 mg(1.38 mmol) of sodium borohydride. After 3 hours at room temperature,the reaction is halted by adding water. It is extracted with ethylacetate, the combined organic phases are washed with saturated sodiumchloride solution and dried on sodium sulfate. After removal of thesolvent and chromatography on silica gel with hexane-ethyl acetate(0-100%), 94 mg (55% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 3H), 1.56 (s, 3H), 2.19 (s, 3H),2.35 (d, 1H), 2.77 (d, 1H), 3.10-3.16 (m, 2H), 3.31 (dd, 1H), 3.84 (s,3H), 4.28 (dd, 1H), 5.36 (s, 2H), 6.07 (d, 1H), 6.80 (dd, 1H), 6.91-6.98(m, 1H), 7.11 (dd, 1H), 7.37-7.53 (m, 3H), 7.99 (d, 1H).

Example 51

4-(5-Fluoro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

In the reaction of 170 mg (0.34 mmol) of1-(2-(acetoxymethyl)quinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-olwith 53 mg (1.38 mmol) of sodium borohydride in 1.5 ml of methanol and0.8 ml of tetrahydrofuran, 43 mg (27% of theory) of the product isobtained (cf. Example 14).

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 3H), 1.57 (s, 3H), 2.35 (d, 1H),2.77 (d, 1H), 3.10-3.16 (m, 2H), 3.32 (dd, 1H), 3.84 (s, 3H), 4.29 (dd,1H), 4.41 (br, 1H), 4.89 (s, 2H), 6.07 (d, 1H), 6.79 (dd, 1H), 6.91-6.97(m, 1H), 7.12 (dd, 1H), 7.20 (d, 1H), 7.42-7.51 (m, 2H), 7.95 (d, 1H).

Example 52

4-(5-Fluoro-2-hydroxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

290 mg (0.62 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olin 7.0 ml of dichloromethane is mixed at room temperature with 12.5 ml(12.5 mmol) of a 1 M boron tribromide solution. After 20 hours at roomtemperature, the reaction is brought to a halt by adding methanol. Thesolvent is removed in a vacuum, the residue is taken up in saturatedsodium bicarbonate solution and ethyl acetate, extracted with ethylacetate, and the combined organic phases are dried on sodium sulfate.After the solvent is removed and after purification on silica gel withhexane-ethyl acetate (0-70%) as well as with ethyl acetate-methanol(0-10%), 160 mg (51% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.46 (s, 3H), 1.56 (s, 3H), 1.93 (d, 1H),2.94 (dd, 1H), 3.09-3.21 (m, 2H), 4.67 (d, 2H), 5.34-5.37 (m, 1H), 5.51(t, 1H), 5.91 (d, 1H), 5.98 (s, 1H), 6.73 (dd, 1H), 6.81-6.87 (m, 1H),7.01 (dd, 1H), 7.14 (d, 1H), 7.32 (t, 1H), 7.54 (d, 1H), 8.28 (d, 1H),9.74 (s, 1H).

Example 53

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid methyl ester

5-Aminoquinoline-2-carboxylic acid methyl ester

At 0° C., 2.8 g (mmol) of potassium nitrate is added in portions to asolution that consists of 3.5 g (20.21 mmol) of quinoline-2-carboxylicacid in 12 ml of concentrated sulfuric acid. After 4 days at roomtemperature, the reaction mixture is poured onto ice water. Theprecipitated solid is suctioned off, washed with a little water anddried under high vacuum. The crude product is dissolved in 50 ml ofmethanol. After adding 10 ml of concentrated sulfuric acid, the reactionsolution is allowed to reflux for 4 hours, then stirred for 36 hours atroom temperature. The reaction solution is concentrated by evaporationto one third of the original volume and added to ice water. It isextracted with ethyl acetate, the combined organic phases are washedwith saturated sodium bicarbonate solution, then with saturated sodiumchloride solution, it is dried on sodium sulfate, and the solvent isremoved in a vacuum. The crude product is dissolved in 80 ml ofmethanol-acetone (50%) and mixed with palladium on carbon and potassiumcarbonate. It is stirred for 20 hours under hydrogen atmosphere at roomtemperature. After suctioning off on Celite and washing with acetone,the solvent is removed in a vacuum, and the residue is purified onsilica gel with hexane/ethyl acetate (0-60%). 850 mg (27% of theory) ofthe product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=4.07 (s, 3H), 6.90 (d, 1H), 7.58 (t, 1H),7.75 (d, 1H), 8.12 (d, 1H), 8.33 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]-quinoline-2-carboxylicacid methyl ester

Analogously to Example 37, 200 mg (1.0 mmol) of5-aminoquinoline-2-carboxylic acid methyl ester is reacted with 371 mg(1.2 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 1.10 ml of concentrated acetic acid in 20 ml of toluene. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 420 mg(85% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (s, 3H), 1.59 (s, 3H), 2.29 (d, 1H),3.47 (d, 1H), 3.80 (s, 3H), 4.10 (s, 3H), 4.79 (s, 1H), 6.40-6.45 (m,1H), 6.53-6.56 (m, 2H), 6.81 (dd, 1H), 7.54 (s, 1H), 7.60 (t, 1H), 8.18(d, 1H), 8.23 (d, 1H), 8.45 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid methyl ester

Analogously to Example 40, 420 mg (0.85 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid methyl ester is dissolved in 10 ml ofmethanol and mixed with 130 mg (3.41 mmol) of sodium borohydride. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 75 mg(18% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 3H), 1.56 (s, 3H), 2.36 (d, 1H),2.78 (d, 1H), 3.04 (s, 1H), 3.15 (dd, 1H), 3.50 (dd, 1H), 3.84 (s, 3H),4.08 (s, 3H), 4.35 (dd, 1H), 6.16 (d, 1H), 6.77 (dd, 1H), 6.89-6.95 (m,1H), 7.10 (dd, 1H), 7.52 (t, 1H), 7.71 (d, 1H), 8.11 (s, 2H).

Example 54

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid

A solution that consists of 60 mg (0.12 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyamino]quinoline-2-carboxylicacid methyl ester in 10 ml of methanol is mixed with 0.5 ml (0.5 mmol)of 1N sodium hydroxide solution. After 2.5 hours, the solvent is removedin a vacuum, and the residue is purified on silica gel withdichloromethane-methanol (6-25%). 47 mg (82% of theory) is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.38 (s, 3H), 1.54 (s, 3H), 2.04 (d, 1H),2.91-3.06 (m, 3H), 3.75 (s, 3H), 5.49 (br, 1H), 5.94 (d, 1H), 6.11 (br,1H), 6.83-6.88 (m, 1H), 6.93-6.97 (m, 1H), 7.07 (dd, 1H), 7.34 (t, 1H),7.44 (d, 1H), 8.00 (d, 1)H), 8.38 (d, 1H).

Example 55

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]-quinoline-2-carboxylicacid methylamide

5-Aminoquinoline-2-carboxylic acid methylamide

76 mg (0.376 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester isdissolved with 10 ml of a 2.0 M methanolic methylamine solution. After90 minutes under reflux and another 16 hours at room temperature, thesolvent is removed under reduced pressure, and the residue is purifiedon silica gel with hexane-ethyl acetate (0-80%). 72 mg (95% of theory)of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=2.87 (d, 3H), 6.10 (s, 2H), 6.77 (d, 1H),7.27 (d, 1H), 7.51 (t, 1H), 7.95 (d, 1H), 8.68 (d, 1H), 8.79-8.80 (m,1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino]-quinoline-2-carboxylicacid methylamide

Analogously to Example 37, 220 mg (1.08 mmol) of5-aminoquinoline-2-carboxylic acid-methylamide is reacted with 550 mg(1.78 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 3.0 ml of concentrated acetic acid in 30 ml of toluene. Afterchromatography on silica gel with hexane-ethyl acetate (0-70%), 259 mg(48% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.56 (s, 3H), 2.29 (d, 1H),3.11 (d, 3H), 3.48 (d, 1H), 3.81 (s, 3H), 4.81 (s, 1H), 6.46-6.49 (m,2H), 6.57 (dd, 1H), 6.78 (dd, 1H), 7.50 (s, 1H), 7.56 (t, 1H), 7.95 (d,1H), 8.23 (br, 1H), 8.34 (d, 1H), 8.46 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]-quinoline-2-carboxylicacid methylamide

155 mg (0.315 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid methylamide is dissolved in 10 ml of ethanol and mixed with 0.09 ml(0.4 mmol) of titanium tetraethylate as well as 94 mg (2.6 mmol) ofsodium borohydride. The reaction is halted after 5 hours by addingsaturated sodium chloride solution and ethyl acetate. Insolublecomponents are filtered. The filtrate is extracted with ethyl acetate,the combined organic phases are dried on sodium sulfate, and the solventis removed in a vacuum. After chromatography on silica gel withhexane-ethyl acetate (0-50%), 110 mg (71% of theory) of the product isobtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.38 (s, 3H), 1.56 (s, 3H), 2.06 (d, 1H),2.86-2.97 (m, 5H), 3.07 (dd, 1H), 3.78 (s, 3H), 5.98 (s, 1H), 6.03 (d,1H), 6.86-7.05 (m, 2H), 7.07 (dd, 1H), 7.32 (d, 1H), 7.46 (t, 1H), 8.03(d, 1H), 8.49 (d, 1H), 8.81 (q, 1H).

Example 56

5-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]-quinoline-2-carboxylicacid methylamide

Analogously to Example 38, 97 mg (0.197 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid methylamide is reacted with 8.0 ml (8.0 mmol) of a 1 M borontribromide solution. After working-up and purification on silica gelwith hexane-ethyl acetate (0-70%), 18 mg (18% of theory) of the productis obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.40 (s, 3H), 1.57 (s, 3H), 1.93 (d, 1H),2.87 (d, 3H), 2.97 (dd, 1H), 3.13-3.20 (m, 2H), 5.51-5.54 (m, 1H), 5.98(s, 1H), 6.04 (d, 1H), 6.67 (dd, 1H), 6.76-6.83 (m, 1H), 7.00 (dd, 1H),7.32 (d, 1H), 7.45 (t, 1H), 8.03 (d, 1H), 8.46 (d, 1H), 8.80-8.82 (m,1H), 9.72 (br, 1H).

Example 57

4-(4-Chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

5-[4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid methyl ester

Analogously to Example 1, 250 mg (1.24 mmol) of5-aminoquinoline-2-carboxylic acid methyl ester is reacted with 484 mg(1.49 mmol) of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 1.40 ml of concentrated acetic acid in 20 ml of toluene. Afterchromatography on silica gel with hexane-ethyl acetate (0-100%), 500 mg(79% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.36 (s, 3H), 1.58 (s, 3H), 2.28 (d, 1H),3.45 (d, 1H), 3.84 (s, 3H), 4.11 (s, 3H), 4.79 (s, 1H), 6.38 (d, 1H),6.48 (dd, 1H), 6.67 (d, 1H), 7.00 (d, 1H), 7.52 (s, 1H), 7.65 (dd, 1H),8.18-8.25 (m, 2H), 8.48 (d, 1H).

4-(4-Chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 40, 200 mg (0.39 mmol) of5-[4-(4-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid methyl ester is dissolved in 5.0 ml of methanol and mixed with 60mg (1.56 mmol) of sodium borohydride. After chromatography on silica gelwith hexane-ethyl acetate (0-100%), 70 mg (37% of theory) of the productis obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.37 (s, 3H), 1.55 (s, 3H), 2.04 (d, 1H),2.82-2.91 (m, 2H), 2.98-3.02 (m, 1H), 3.81 (s, 3H), 4.67 (d, 2H),5.39-5.42 (m, 1H), 5.49 (t, 1H), 5.87 (d, 1H), 5.95 (s, 1H), 6.95 (dd,1H), 7.01 (d, 1H), 7.17 (d, 1H), 7.29-7.37 (m, 2H), 7.53-7.55 (d, 1H),8.29 (d, 1H).

Example 58

4-(4-Chloro-2-hydroxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 38, 110 mg (0.23 mmol) of4-(4-chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olis reacted with 4.60 ml (4.60 mmol) of a 1 M boron tribromide solution.After working-up and purification on silica gel with hexane-ethylacetate (0-100%) as well as with ethyl acetate-methanol (0-20%), 54 mg(50% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.39 (s, 3H), 1.57 (s, 3H), 1.94 (d, 1H),2.91 (dd, 1H), 3.04-3.13 (m, 2H), 4.67 (d, 2H), 5.34-5.37 (m, 1H), 5.50(t, 1H), 5.87 (d, 1H), 5.97 (s, 1H), 6.80-6.83 (m, 2H), 7.16 (d, 1H),7.34 (t, 1H), 7.53 (d, 1H), 8.27 (d, 1H), 10.20 (s, 1H).

Example 59

4-(5-Chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

5-[4-(5-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid methyl ester

224 mg (0.69 mmol) of4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 195 mg (0.96 mmol) of 5-aminoquinoline-2-carboxylic acid methylester are dissolved in 20 ml of toluene. After 5.0 ml of concentratedacetic acid is added, it is refluxed for 16 hours in a water separator.After the solvent is removed, the residue is taken up in 10 ml oftetrahydrofuran, 0.3 ml (1.4 mmol) of titanium tetraethylate is added,and the reaction is allowed to reflux again. After the solvent isremoved as well as after purification on silica gel with hexane/ethylacetate (0-100%), 120 mg (33% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.51 (t, 3H), 1.57 (s, 3H),2.99 )d, 1H), 3.49 (d, 1H), 3.81 (s, 3H), 4.57 (q, 2H), 4.83 (s, 1H),6.52-6.58 (m, 1H), 6.79 (dd, 1H), 7.02 (d, 1H), 7.51 (s, 1H), 7.61 (t,1H), 8.18-8.26 (m, 2H), 8.46 (d, 1H).

4-(5-Chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 40, 120 mg (0.23 mmol) of5-[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]-quinoline-2-carboxylicacid ethyl ester is reacted with 35 mg (0.92 mmol) of sodiumborohydride. After working-up and purification on silica gel withhexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol(0-20%), 61 mg (55% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.47 (s, 3H), 1.59 (s, 3H), 2.29 (d, 1H),2.82 (d, 1H), 3.05-3.16 (m, 2H), 3.29-3.36 (m, 1H), 4.23-4.26 (m, 1H),4.32-4.52 (br, 1H), 4.88 (s, 2H), 6.04-6.06 (m, 1H), 6.79 (d, 1H),7.18-7.21 (m, 2H), 7.36 (d, 1H), 7.48-7.50 (m, 2H), 7.95 (d, 1H).

Example 60

3-[1-(5-Fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-(hydroxymethyl)quinolin-5-ylamino)-2-(trifluoroethyl)propan-2-ol

5-{3-[1-(5-Fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propylidenamino}quinoline-2-carboxylicacid methyl ester

Analogously to Example 37, 306 mg (1.2 mmol) of5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanalis reacted with 170 mg (0.84 mmol) of 5-aminoquinoline-2-carboxylic acidmethyl ester in 4.0 ml of concentrated acetic acid and 20 ml of toluene.After working-up and purification on silica gel with hexane-ethylacetate (0-70%), 204 mg (49% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=0.61-0.68 (m, 1H), 0.76-0.80 (m, 1H),0.94-1.00 (m, 1H), 1.06-1.12 (m, 1H), 2.16 (d, 1H), 2.90 (d, 1H), 3.84(s, 3H), 4.10 (s, 3H), 4.82 (s, 1H), 6.58 (d, 1H), 6.63-6.66 (m, 2H),6.75 (d, 1H), 7.63 (t, 1H), 7.74 (s, 1H), 8.19-8.26 (m, 2H), 8.60 (d,1H).

3-[1-(5-Fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-(hydroxymethyl)quinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol

Analogously to Example 40, 200 mg (0.41 mmol) of5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propylidenamino}-quinoline-2-carboxylicacid methyl ester is reacted with 156 mg (4.1 mmol) of sodiumborohydride. After working-up and purification on silica gel withhexane-ethyl acetate (0-75%), 119 mg (63% of theory) of the product isobtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=0.58-0.61 (m, 1H), 0.78-0.91 (m, 3H), 1.90(d, 1H), 2.65 (d, 1H), 3.17-3.18 (m, 2H), 3.61 (s, 3H), 4.68 (d, 2H),5.31 (t, 1H), 5.51 (t, 1H), 5.97 (s, 1H), 6.13 (d, 1H), 6.61 (dd, 1H),6.85 (td, 1H), 7.01 (dd, 1H), 7.17 (d. 1H), 7.38 (t, 1H), 7.54 (d, 1H),8.37 (d, 1H).

Example 61

3-[1-(5-Fluoro-2-hydroxyphenyl)cycloprop-1-yl]-1-(2-(hydroxymethyl)quinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol

Analogously to Example 38, 100 mg (0.22 mmol) of3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-(hydroxymethyl)quinolin-5-ylamino)-2-(trifluoromethyl)propan-2-olis reacted with 4.40 ml (4.40 mmol) of a 1 M boron tribromide solution.After working-up and purification on silica gel with hexane-ethylacetate (0-100%) as well as with ethyl acetate-methanol (0-20%), 50 mg(50% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=0.66-0.73 (m, 1H), 0.83-0.88 (m, 3H), 2.04(d, 1H), 2.54 (d, 1H), 3.24-3.26 (m, 2H), 4.68 (d, 2H), 5.32 (t, 1H),5.51 (t, 1H), 5.95 (s, 1H), 6.23 (d, 1H), 6.60 (d, 1H), 6.73-6.79 (m,1H), 6.94 (dd, 1H), 7.16 (d, 1H), 7.39 (t, 1H), 7.54 (d, 1H), 8.33 (d,1H), 9.49 (s, 1H).

Example 62

4-(7-Chlorobenzo[1,3]dioxol-4-yl)-2-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

5-[4-(7-Chlorobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid methyl ester

Analogously to Example 37, 70 mg (0.21 mmol) of4-(7-chlorobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalis reacted with 50 mg (0.25 mmol) of 5-aminoquinoline-2-carboxylic acidmethyl ester in 0.5 ml of concentrated acetic acid and 20 ml of toluene.After working-up and purification on silica gel with hexane-ethylacetate (0-100%), 60 mg (55% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.52 (s, 3H), 2.34 (d, 1H),3.08 (d, 1H), 4.11 (s, 3H), 4.83 (s, 1H), 5.94 (s, 1H), 6.02 (s, 1H),6.37 (d, 1H), 6.54 (t, 1H), 7.58-7.70 (m, 2H), 8.20-8.26 (m, 2H), 8.57(d, 1H).

4-(7-Chlorobenzo[1,3]dioxol-4-yl)-2-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 40, 60 mg (0.11 mmol) of5-[4-(7-chlorobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]-quinoline-2-carboxylicacid methyl ester is reacted with 18 mg (0.46 mmol) of sodiumborohydride. After working-up and purification on silica gel withhexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol(0-20%), 21 mg (39% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.37 (s, 3H), 1.53 (s, 3H), 2.11 (d, 1H),2.55 (d, 1H), 3.01-3.19 (m, 2H), 4.67 (d, 2H), 5.42-5.46 (m, 1H), 5.50(t, 1H), 5.98-6.08 (m, 4H), 6.86 (s, 2H), 7.18 (d, 1H), 7.36 (t, 1H),7.55 (d, 1H), 8.32 (d, 1H).

Example 63

4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

5-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid methyl ester

Analogously to Example 37, 160 mg (0.47 mmol) of4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalis reacted with 116 mg (0.57 mmol) of 5-aminoquinoline-2-carboxylic acidmethyl ester in 1.0 ml of concentrated acetic acid and 20 ml of toluene.After working-up and purification on silica gel with hexane-ethylacetate (0-100%), 110 mg (45% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.34 (s, 3H), 1.55 (s, 3H), 2.27 (d, 1H),2.65-2.73 (m, 1H), 2.91-3.01 (m, 1H), 3.35 (d, 1H), 4.11 (s, 3H),4.42-4.58 (m, 2H), 4.79 (s, 1H), 6.58 (s, 1H), 6.65 (d, 1H), 6.82 (d,1H), 7.61-7.67 (m, 2H), 8.21 (d, 1H), 8.27 (d, 1H), 8.47 (d, 1H).

4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 40, 110 mg (0.21 mmol) of5-[4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]-quinoline-2-carboxylicacid methyl ester is reacted with 32 mg (0.84 mmol) of sodiumborohydride. After working-up and purification on silica gel withhexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol(0-30%), 68 mg (65% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.34 (s, 3H), 1.53 (s, 3H), 2.03 (d, 1H),2.77 (d, 1H), 2.85-3.12 (m, 4H), 5.32-5.36 (m, 1H), 5.51 (t, 1H), 5.96(d, 1H), 6.02 (s, 1H), 7.03 (s, 1H), 7.07 (s, 1H), 7.18 (d, 1H), 7.37(t, 1H), 7.54 (d, 1H), 8.29 (d, 1H).

Example 64

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid diethylamide

5-Aminoquinoline-2-carboxylic acid diethylamide

A suspension that consists of 1.06 g (7.95 mmol) of aluminum chloride in35 ml of toluene is mixed with 1.70 ml (15.7 mmol) of diethylamine whilebeing cooled with ice. After one hour at room temperature, 350 mg (1.73mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is added, andthe reaction mixture is allowed to stir for 5 hours at 40° C. Thereaction is halted by adding water. It is extracted withdichloromethane, and the combined organic phases are dried on sodiumsulfate. After removal of the solvent and purification on silica gelwith dichloromethane-methanol (0-10%), 210 mg (50% of theory) of theproduct is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.11 (t, 3H), 1.19 (t, 3H), 3.27 (q, 2H),3.48 (q, 2H), 6.06 (s, 2H), 6.74 (d, 1H), 7.17 (d, 1H), 7.42-7.47 (m,2H), 8.61 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid diethylamide

A solution that consists of 210 mg (0.86 mmol) of5-aminoquinoline-2-carboxylic acid diethylamide, 266 mg (0.86 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 0.36 ml (1.73 mmol) of titanium tetraethylate in 15 ml oftetrahydrofuran is stirred for one hour at room temperature and then for3 hours at 80° C. After removal of the solvent and purification onsilica gel with hexane-ethyl acetate (0-70%), 230 mg (52% of theory) ofthe product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.23 (t, 3H), 1.33 (t, 3H), 1.37 (s, 3H),1.57 (s, 3H), 3.38-3.50 (m, 3H), 3.63 (q, 2H), 3.81 (s, 3H), 4.82 (s,1H), 6.43-6.50 (m, 2H), 6.56 (dd, 1H), 6.79 (dd, 1H), 7.50 (s, 1H), 7.55(t, 1H), 7.68 (d, 1H), 7.99 (d, 1H), 8.39 (d, 1H).

5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid diethylamide

A solution that consists of 230 mg (0.45 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid diethylamide and 0.132 ml (0.58 mmol) of titanium tetraethylate in14 ml of ethanol is mixed with 135 mg (3.55 mmol) of sodium borohydride.After 6 hours at room temperature, the reaction is halted by addingsaturated sodium chloride solution and ethyl acetate. The precipitatethat is produced is suctioned off on Celite. The filtrate is washed withsaturated sodium chloride solution, and it is dried on sodium sulfate.After removal of the solvent and purification on silica gel withhexane-ethyl acetate (0-70%), 220 mg (92%) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.20 (t, 3H), 1.31 (t, 3H), 1.46 (s, 3H),1.56 (s, 3H), 2.34 (d, 1H), 2.78 (d, 1H), 3.13 (dd, 1H), 3.19 (s, 1H),3.31 (dd, 1H), 3.41 (q, 2H), 3.60 (q, 2H), 3.84 (s, 3H), 4.33-4.37 (m,1H), 6.08 (d, 1H), 6.79 (dd, 1H), 6.89-6.96 (m, 1H), 7.11 (dd, 1H),7.42-7.51 (m, 2H), 7.55 (d, 1H), 8.03 (d, 1H).

Example 65

5-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]-quinoline-2-carboxylicacid diethylamide

210 mg (0.39 mmol) of5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylicacid diethylamide is mixed with 7.8 ml (7.8 mmol) of a 1 M borontribromide solution in dichloromethane. After 20 hours at roomtemperature, the reaction is halted by adding water. It is extractedwith ethyl acetate, the combined organic phases are washed withsaturated sodium bicarbonate solution, and it is dried on sodiumsulfate. After the solvent is removed and after purification on silicagel with hexane-ethyl acetate (0-100%), 56 mg (28%) of the product isobtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.10 (t, 3H), 1.19 (t, 3H), 1.40 (s, 3H),1.57 (s, 3H), 1.93 (d, 1H), 2.96 (dd, 1H), 3.11-3.29 (m, 4H), 3.48 (q,2H), 5.48-5.52 (m, 1H), 5.97 (s, 1H), 6.01 (d, 1H), 6.70 (dd, 1H),6.79-6.85 (m, 1H), 7.00 (dd, 1H), 7.22 (d, 1H), 7.41 (t, 1H), 7.51 (d,1H), 8.40 (d, 1H), 9.73 (s, 1H).

Example 66

4-(5-Fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

2-Bromomethyl-5-nitroquinoline

A solution that consists of 800 mg (4.25 mmol) of5-nitro-2-methylquinoline in 20 ml of tetrachloromethane is mixed with11 mg (0.04 mmol) of benzoyl peroxide and 794 mg (4.46 mmol) ofN-bromosuccinimide. The reaction mixture is allowed to reflux for 8hours in the presence of UV light. Insoluble components are filteredoff, and the filtrate is concentrated by evaporation. After purificationon silica gel with hexane-ethyl acetate (0-100%), 320 mg (28% of theory)of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=4.72 (s, 2H), 7.79-7.82 (m, 2H), 8.35-8.39(m, 2H), 9.02 (d, 1H).

2-(Morpholin-4-ylmethyl)-5-nitroquinoline

460 mg (1.72 mmol) of 2-bromomethyl-5-nitroquinoline and 0.54 ml (6.2mmol) of morpholine are dissolved in 150 ml of toluene. After 1.07 g(7.74 mmol) of potassium carbonate is added, the reaction mixture isallowed to reflux for 2 hours. Potassium carbonate is filtered off, andthe filtrate is concentrated by evaporation. After purification onsilica gel with hexane-ethyl acetate (0-100%), 190 mg (40% of theory) ofthe product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.55-2.58 (m, 4H), 3.74-3.77 (m, 4H), 3.86(s, 2H), 7.78 (t, 1H), 7.87 (d, 1H), 8.33-8.39 (m, 2H), 8.95 (d, 1H).

5-Amino-2-(morpholin-4-ylmethyl)quinoline

190 mg (0.7 mmol) of 2-(morpholin-4-ylmethyl)-5-nitroquinoline isdissolved in 10 ml of methanol. After the addition of 19 mg of palladiumon carbon and 19 mg of potassium carbonate, the reaction mixture isallowed to stir for 4 hours at room temperature under hydrogenatmosphere. It is then filtered on Celite and washed with ethyl acetate.After removal of the solvent in a vacuum and chromatography on silicagel with hexane-ethyl acetate (0-100%) as well as with ethylacetate-methanol (0-100%), 134 mg (79% of theory) of the product isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.55-2.57 (m, 4H), 3.73-3.76 (m, 4H), 3.82(s, 2H), 4.18 (br, 2H), 6.79 (d, 1H), 7.45-7.59 (m, 3H), 8.14 (d, 1H).

4-(5-Fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylimino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 37, 180 mg (0.74 mmol) of5-amino-2-(morpholin-4-ylmethyl)quinoline is reacted with 274 mg (0.89mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalin 0.8 ml of concentrated acetic acid and 20 ml of toluene. Afterpurification on silica gel with hexane-ethyl acetate (0-100%), 220 mg(56% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.57 (s, 3H), 2.29 (d, 1H),2.55-2.58 (m, 4H), 3.46 (d, 1H), 3.75-3.77 (m, 4H), 3.80 (s, 3H), 3.85(s, 2H), 4.88 (s, 1H), 6.38-6.45 (m, 2H), 6.53 (dd, 1H), 6.79 (dd, 1H),7.47-7.52 (m, 2H), 7.67 (d, 1H), 7.94 (d, 1H), 8.28 (d, 1H).

4-(5-Fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 40, 220 mg (0.41 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olis dissolved in 10 ml of methanol and mixed with 315 mg (8.25 mmol) ofsodium borohydride. After working-up and purification, 109 mg (50% oftheory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 3H), 1.56 (s, 3H), 2.34 (d, 1H),2.52-2.55 (m, 4H), 2.77 (d, 1H), 3.09-3.16 (m, 2H), 3.31 (dd, 1H),3.72-3.75 (m, 4H), 3.81 (s, 2H), 3.85 (s, 3H), 4.26-4.29 (m, 1H), 6.05(d, 1H), 6.81 (dd, 1H), 6.91-6.98 (m, 1H), 7.11 (dd, 1H), 7.39-7.56 (m,3H), 7.94 (d, 1H).

Example 67

4-(5-Fluoro-2-hydroxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 38, 80 mg (0.15 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(2-(morpholin-4-ylmethyl)quinolin-5-ylamino)-4-methyl-2-trifluoromethyl)pentan-2-olis mixed with 3.0 ml (3.0 mmol) of a 1 M boron tribromide solution indichloromethane. After working-up and purification on silica gel withhexane-ethyl acetate (0-100%) as well as ethyl acetate-methanol (0-20%),53 mg (68% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.40 (s, 3H), 1.56 (s, 3H), 2.40-2.43 (m,4H), 2.93 (dd, 1H), 3.09-3.20 (m, 2H), 3.58-3.61 (m, 4H), 3.69 (s, 2H),5.33-5.37 (m, 1H), 5.93 (d, 1H), 5.96 (br, 1H), 6.72 (dd, 1H), 6.80-6.86(m, 1H), 6.99 (dd, 1H), 7.17 (d, 1H), 7.32 (t, 1H), 7.51 (d, 1H), 8.24(d, 1H), 9.74 (br, 1H).

Example 68

5-[4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]-quinoline-2-carboxylicacid amide

5-[4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]-quinoline-2-carboxylicacid amide

Analogously to Example 37, 160 mg (0.87 mmol) of5-aminoquinoline-2-carboxylic acid amide is reacted with 341 mg (1.05mmol) of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalin 0.96 ml of concentrated acetic acid and 20 ml of toluene. Afterpurification on silica gel with hexane-ethyl acetate (0-100%), 340 mg(79% of theory) of the product is obtained.

¹H-NMR (300 MHz, CDCl₃): δ=1.37 (s, 3H), 1.58 (s, 3H), 2.27 (d, 1H),3.44 (d, 1H), 3.84 (s, 3H), 4.80 (s, 1H), 5.71 (br, 1H), 6.39 (d, 1H),6.44 (dd, 1H), 6.66 (d, 1H), 6.99 (d, 1H), 7.51 (s, 1H), 7.62 (dd, 1H),7.99 (d, 1H), 8.07 (br, 1H), 8.33 (d, 1H), 8.49 (d, 1H).

5-[4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]-quinoline-2-carboxylicacid amide

Analogously to Example 40, 340 mg (0.69 mmol) of5-[4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylicacid amide is dissolved in 10 ml of methanol and mixed several timeswith 110 mg (2.89 mmol) of sodium borohydride. After working-up andpurification on silica gel with hexane-ethyl acetate (0-100%), 280 mg(82% of theory) of the product is obtained.

¹H-NMR (300 MHz, DMSO-d₆): δ=1.37 (s, 3H), 1.56 (s, 3H), 2.06 (d, 1H),2.85-3.06 (m, 3H), 3.81 (s, 3H), 5.57-5.61 (m, 1H), 5.96 (s, 1H), 6.00(d, 1H), 6.95 (dd, 1H), 6.98 (d, 1H), 7.29-7.35 (m, 2H), 7.46 (t, 1H),7.71 (br, 1H), 8.04 (d, 1H), 8.21 (br, 1H), 8.48 (d, 1H).

Example 69

5-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}isoquinolin-1(2H)-one

a. 2-Methyl-3-nitrobenzoic acid methyl ester

20 g (110.4 mmol) of 2-methyl-3-nitrobenzoic acid is refluxed in 100 mlof methanol for 10 hours after 2 ml of concentrated sulfuric acid isadded. The product that crystallizes out during cooling is suctioned offand dried. The filtrate is evaporated to the dry state, the solidresidue is taken up in ethyl acetate, and the solution is washed twicewith saturated sodium bicarbonate solution. After drying on Na₂SO₄,another product is obtained. Together, 16.4 (76.3%) of the desiredcompound is obtained.

b. 5-Nitroisocoumarin

16.4 g (84.03 mmol) of the compound that is described under a is stirredwith 26.8 g (225.1 mmol) of N,N-dimethylformamide dimethylacetal in 85ml of dimethylformamide for 12 hours at 130° C. The solvent is drawn offin a rotary evaporator, the residue is taken up in methyl-tert-butylether and washed three times with water. After washing with saturatedNaCl solution, the organic phase is dried. After the desiccant isfiltered off and the solvent is spun off, the remaining residue ischromatographed on silica gel (mobile solvent ethyl acetate/hexane).8.73 g (54.5%) of the desired compound is isolated.

MS (CI) m/e (relative intensity): 209 (M⁺¹⁸, 52), 191 (M⁺, 29), 179(100).

c. 5-Nitroisoquinolin-1(2H)-one

2.51 g (13.13 mmol) of 5-nitroisocoumarin is added to 100 ml of ethanol.Ammonia is pressure-forced in in an autoclave. The product precipitatesand is suctioned off. 1.98 g (79.7%) of the desired compound isisolated.

MS (CI) m/e (relative intensity): 208 (M⁺¹⁸, 60), 191 (M⁺¹, 100), 161(81).

d. 5-Aminoisoquinolin-1(2H)-one

268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one is added with 376.5mg of ammonium chloride and 2.6 ml of water in 14 ml of ethanol and 5.4ml of tetrahydrofuran. After the addition of 1.23 g of zinc powder inportions (heating to 30 to 35° C.), it is stirred for two hours. Thereaction mixture is suctioned off via a glass fiber filter and rewashedwith ethyl acetate. After the filtrate is washed with water andsaturated sodium chloride solution, the organic phase is dried as usual.Filtering off the desiccant and spinning-off the solvent produce 196.5mg (88.1%) of the desired amine.

MS (CI) m/e (relative intensity): 161 (M⁺¹, 100).

e.5-{(E/Z)-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one

140.1 mg (0.455 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalis stirred with 72.8 mg (0.455 mmol) of 5-aminoisoquinolin-1(2H)-one in0.74 ml of glacial acetic acid overnight. The mixture is evaporated tothe dry state, and the residue is put on a Flashmaster column (mobilesolvent ethyl acetate/hexane). 103.6 mg (52.5%) of the desired compoundis isolated.

MS (ES+) m/e (relative intensity): 451 (M⁺¹, 100).

f.5-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}isoquinolin-1(2H)-one

103.6 mg (0.239 mmol) of the compound that is described under e. ismixed with 2.6 ml of dichloroethane and 0.1 ml of glacial acetic acid.After 75.9 mg (0.359 mmol) of sodium triacetoxy borohydride is added, itis stirred overnight. The reaction mixture is mixed with saturatedsodium bicarbonate solution and extracted twice with ethyl acetate. Thecombined organic phases are washed with water and saturated sodiumchloride solution, dried, filtered and concentrated by evaporation.After chromatography on a Flashmaster (mobile solvent ethylacetate/hexane), 36 mg (34.6%) of the desired compound is isolated.

MS (ES+) m/e (relative intensity): 453 (M⁺¹, 100).

Example 70

5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentyl]amino}isoquinolin-1(2H)-one

30 mg (0.066 mmol) of the compound that is synthesized under Example 70f. is mixed with 0.76 ml of a 1 M solution of boron tribromide indichloromethane. After four hours of stirring at room temperature, thereaction mixture is diluted with ethyl acetate and washed once withsaturated sodium bicarbonate solution. After the organic phase (sodiumsulfate) is dried, the solvent is spun off after the desiccant isfiltered off. Chromatography on a Flashmaster (mobile solvent ethylacetate/hexane) yields 15.9 mg (56.7%) of the desired compound.

MS (ES+) m/e (relative intensity): 439 (M⁺¹, 100).

Similarly produced starting from the corresponding aldehydes were:

-   5-{[4-(3-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}isoquinolin-1(2H)-one-   5-({3-[1-(3-Fluoro-2-hydroxyphenyl)cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propyl}amino)isoquinolin-1(2H)-one-   5-{[4-(4-Chloro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}isoquinolin-1(2H)-one-   5-{[4-(5-Chloro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}isoquinolin-1(2H)-one-   5-{[4-(2-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}isoquinolin-1(2H)-one-   (+)-5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}isoquinolin-1(2H)-one-   (−)-5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}isoquinolin-1(2H)-one

Example 71

5-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-2,6-dimethyl-quinoline

a. 2,6-Dimethyl-5-nitroquinoline

3 g (19.08 mmol) of 2,6-dimethylquinoline is introduced into 15 ml ofconcentrated sulfuric acid at 10° C. After one-half hour, a solution of2.03 g of potassium nitrate in 11.4 concentrated sulfuric acid is addedin drops, specifically so that the temperature remains between 5° and15° C. The batch is stirred for one more hour and then poured onto icewater. It is made ammonia-alkaline, and the deposited precipitate issuctioned off. After washing with water, the crude product is dissolvedin ethyl acetate and shaken from water. The organic phase is treated asusual. After the solvent is spun off, 3.69 g (95.6%) of the desiredcompound remains, which is used in the reduction without furtherpurification.

MS (CI) m/e (relative intensity): 220 (M⁺¹⁸, 20), 203 (M⁺¹, 100).

b. 5-Amino-2,6-dimethylquinoline

3.69 g (18.248 mmol) of the compound that is produced according to a. isstirred with 15.19 g (66.85 mmol) of tin(II) chloride dihydrate and 30.4ml of concentrated hydrochloric acid for 45 minutes at 85° C. The batchis poured onto ice water, made basic with 2N NaOH, and the amine isextracted with ethyl acetate. The organic extracts are washed withbrine, dried on sodium sulfate, and the solvent is spun off after thedesiccant is suctioned off. The remaining residue is chromatographed onsilica gel (mobile solvent ethyl acetate/hexane). 2.75 g (87.6%) of thedesired compound is isolated.

MS (ES+) m/e (relative intensity): 173 (M⁺¹, 100).

c.5-{(E/Z)-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}2,6-dimethylquinoline

250 mg (0.811 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanalis refluxed with 139.7 mg (0.811 mmol) of 5-amino, 2,6-dimethylquinolinein ten milliliters of dichloroethane with the addition of 0.2 ml oftrifluoroacetic acid and 150 mg of molecular sieve (4 A) for seven days.The mixture is filtered on a glass fiber filter, and the filtrate isevaporated to the dry state. The residue is put on a Flashmaster column(mobile solvent ethyl acetate/hexane). 134.3 mg (35.8%) of the desiredcompound is isolated.

MS (ES+) m/e (relative intensity): 463 (M⁺¹, 100).

d.5-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}2,6-dimethylquinoline

134.3 mg (0.29 mmol) of the compound that is described under c. is addedto 17 ml of methanol and mixed with 1.7 ml of glacial acetic acid. After141.5 mg (2.252 mmol) of sodium cyanoborohydride is added, it is stirredfor four hours. The reaction mixture is mixed with saturated sodiumbicarbonate solution and extracted twice with ethyl acetate. Thecombined organic phases are washed with water and saturated sodiumchloride solution, dried, filtered, and concentrated by evaporation.After chromatography on a Flashmaster (mobile solvent ethylacetate/hexane), 80 mg (59.3%) of the desired compound is isolated.

MS (ES+) m/e (relative intensity): 465 (M⁺¹, 100).

Example 72

5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-2,6-dimethyl-quinoline

80 mg (0.172 mmol) of the compound that is synthesized under Example71d. is mixed with two milliliters of a 1 M solution of boron tribromidein dichloromethane. After five hours of stirring at room temperature,the reaction mixture is diluted with ethyl acetate and washed once withsaturated sodium bicarbonate solution. The organic phase is dried(sodium sulfate), and the solvent is spun off after the desiccant isfiltered off. Chromatography on a Flashmaster (mobile solvent ethylacetate/hexane) yields 58.9 mg (75.9%) of the desired compound.

MS (ES+) m/e (relative intensity): 451 (M⁺¹, 100).

Similarly synthesized starting from the corresponding aldehydes andamines were the following compounds:

-   (+)-5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}-2,6-dimethylquinoline-   (−)-5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}-2,6-dimethylquinoline-   5-{[4-(3-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}-2,6-dimethylquinoline-   5-{[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}-6-chloro-2-methylquinoline-   5-{[4-(3-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)    pentyl]amino}6-chloro-2-methylquinoline

Example 73

3-[1-(2,5-Difluorophenyl)-cycloprop-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1-(2-methylquinolin-5-ylamino)-propan-2-ol

Analogously to Example 76, 60 mg (1.46 mmol) of NaH (60%) and 244 mg(1.23 mmol) of 5-acetylamino-2-methyl-quinoline are reacted with 365 mg(0.81 mmol) of toluene-4-sulfonicacid-3-[1-(2,5-difluorophenyl)-cycloprop-1-yl]-2-(trifluoromethyl)-2-hydroxy-propylester. The crude product is treated analogously to Example 76 with 1 Msodium hydroxide solution. After chromatography on silica gel withhexane-ethyl acetate (30-50%), 67 mg of product is obtained.

H-NMR (CDCl₃); δ=0.80-1.02 (m, 4H), 2.16 (d, 1H), 2.42 (d, 1H), 2.21 (s,3H), 3.27-3.42 (m, 2H), 4.21-4.30 (m, 1H), 6.30 (dd, 1H), 6.66-6.81 (m,2H), 6.95-7.05 (m, 1H), 7.22 (d, 1H), 7.40-7.50 (m, 2H), 7.96 (d, 1H).

MS (ESI): 437 (M+H).

Example 74

4-(2,5-Difluorophenyl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl-pentan-2-ol

175 mg (0.62 mmol) of4-(2,5-difluorophenyl)-4-methyl-2-(trifluoromethyl)-pentanal and 125 mg(0.78 mmol) of 5-amino-2-methylquinoline are stirred in 10 ml of tolueneand 3 ml of acetic acid for 18 hours at room temperature and refluxedfor another 2 hours in a water separator. The crude product is reducedanalogously to 79 with 120 mg (3.16 mmol) of NaBH₄ in 5 ml of aceticacid. After chromatography on silica gel with hexane-ethyl acetate(30%), 45 mg of product is obtained.

MS (EI): 438 (M⁺).

Example 75

3-[1-(2-Chloro-5-fluorophenyl)cyclobut-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-propan-2-ol

Analogously to Example 79, 200 mg (0.64 mmol) of3-[1-(2-chloro-5-fluorophenyl)cyclobut-1-yl]-2-(trifluoromethyl)-propanaland 126 mg (0.80 mmol) of 5-amino-2-methylquinoline are reacted, and theisolated crude product is reduced with 102 mg (2.70 mmol) of NaBH₄.After chromatography on silica gel with hexane-ethyl acetate, 165 mg ofproduct is obtained.

MS (ESI): 467 (M+H); angle of rotation of the pure (−)-enantiomer afterseparation by chiral HPLC: α_(D)=−31.4.

OTHER EXAMPLES

Synthesis of the Diol Precursors:

Diol-Example a4-(7-Bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol

2,3-Dihydroxy-4-nitrobenzaldehyde:

17.2 g of 2-hydroxy-3-methoxy-4-nitrobenzaldehyde (J. Het. Chem. 33,(1996), 1171) in 350 ml of dichloromethane is slowly mixed at 0° C. with175 ml of boron tribromide solution (1 M in dichloromethane), and it isstirred for another 4 hours. The batch is added to ice water, theorganic phase is separated, and the aqueous phase is extracted withdichloromethane. The combined organic phases are washed with water, andthe solvent is removed in a vacuum. 15.2 g of2,3-dihydroxy-4-nitrobenzaldehyde is obtained as a red solid, flashpoint 122-126° C.

7-Nitro-benzo[1,3]dioxole-4-carboxylic acid:

14.2 g of 2,3-dihydroxy-4-nitrobenzaldehyde in 1000 ml of DMF is stirredwith 57.6 ml of bromochloromethane and 50.6 g of cesium carbonate at100° C. for 7 hours. The batch is added to 1 N hydrochloric acid andextracted with ethyl acetate. The organic phase is washed several timeswith water and brine, dried with sodium sulfate and concentrated byevaporation in a vacuum. The brown solid that is obtained is purified bycolumn chromatography (silica gel, hexane/ethyl acetate 100:0→60:40).7.4 g of 7-nitro-benzo[1,3]dioxole-4-carbaldehyde is obtained as a lightyellow solid. The latter is mixed in 400 ml of acetone at 10° C. with asolution of 11.8 g of potassium permanganate in 190 ml of acetone/water(1:1). It was stirred for 10 hours, added to 2 N hydrochloric acid andfiltered through diatomaceous earth. The acetone is removed in a vacuum,and the aqueous phase is made alkaline with sodium hydroxide solution.It is extracted with ether, and then the aqueous phase is acidified withhydrochloric acid. It is extracted with ethyl acetate, washed withwater, dried with sodium sulfate and concentrated by evaporation in avacuum. 4.36 g of7-nitro-benzo[1,3]dioxole-4-carboxylic acid is obtainedas a brown solid, flash point 230-239° C.

7-Amino-benzo[1,3]dioxole-4-carboxylic acid:

8.05 g of 7-nitro-benzo[1,3]dioxole-4-carboxylic acid is reacted withhydrogen in 650 ml of ethanol with 800 mg of palladium/carbon catalystunder normal pressure at room temperature. It is filtered throughdiatomaceous earth and concentrated by evaporation in a vacuum. 6.82 gof 7-amino-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brownsolid, flash point 196-197° C.

2-(7-Bromo-1,3-benzodioxol-4-yl)-propan-2-ol:

1.95 g of 7-amino-benzo[1,3]dioxole-4-carboxylic acid in 25 ml ofhydrobromic acid (48%) and 20 ml of water are mixed at 0° C. with asolution of 760 mg of sodium nitrite in 4.2 ml of water. It is stirredfor 15 minutes and then added to a solution of 2.07 g of copper(I)bromide in 5.5 ml of hydrobromic acid (48%). It is heated for 30 minutesto 100° C., added to water and extracted with ethyl acetate. It iswashed with brine, dried with sodium sulfate and concentrated byevaporation in a vacuum. 2.88 g of7-bromo-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brownsolid. The latter is reacted in 50 ml of DMF at 0° C. with 4.08 g ofcesium carbonate and 0.8 ml of methyl iodide. It is stirred for 4 hoursat room temperature, added to water, and extracted with ethyl acetate.It is washed several times with water and brine, dried and concentratedby evaporation in a vacuum. 1.81 g of7-bromo-benzo[1,3]dioxole-4-carboxylic acid methyl ester is obtained asa red solid. The latter is dissolved in 5 ml of ether, and 10 ml of THFis added to a solution of 5.06 ml of methylmagnesium chloride (3 M inTHF) and 6 ml of ether at room temperature. After 3.5 hours, the batchis added to 1N hydrochloric acid, extracted with ethyl acetate, washedwith brine, dried and concentrated by evaporation in a vacuum. 1.79 g of2-(7-bromo-1,3-benzodioxol-4-yl)-propan-2-ol is obtained as anorange-colored oil.

¹H-NMR (CDCl₃), δ (ppm)=1.58 (s, 6H), 6.05 (s, 2H), 6.85 (d, 1H), 6.97(d, 1H).

4-(7-Bromobenzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-valeric acid:

1.77 g of 2-(7-bromobenzo[1,3]dioxol-4-yl)-propan-2-ol and 2.82 g of2-trimethylsilyloxy-acrylic acid-ethyl ester (WO 00/32584) in 36 ml ofdichloromethane are mixed at −70° C. with 1.10 ml of tin(VI)chloride. Itis stirred for 20 minutes at −70° C. and then added to saturated sodiumcarbonate solution. It is extracted with dichloromethane, washed withwater, dried and concentrated by evaporation in a vacuum. 3.15 g of4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl esteris obtained as a crude product. The latter is reacted for 4 hours atroom temperature in 57 ml of a mixture that consists of 1N sodiumhydroxide solution in ethanol/water. The batch is added to water,extracted with ether and then the aqueous phase is acidified withhydrochloric acid. It is extracted with ethyl acetate, washed withwater, dried with sodium sulfate and concentrated by evaporation in avacuum. 2.1 g of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valericacid is obtained as a yellow oil.

¹H-NMR (CDCl₃), δ (ppm)=1.46 (s, 6H), 3.44 (s, 2H), 5.98 (s, 2H), 6.66(d, 1H), 6.94 (d, 1H).

4-(7-Bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-ventan-1-ol:

300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acidand 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4hours to 70° C. Then, the batch is concentrated by evaporation in avacuum and added to water. It is extracted with ethyl acetate, washedwith brine, dried and concentrated by evaporation in a vacuum. 272 mg of4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl esteris obtained as a yellow oil. This ester and 0.32 ml oftrifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml ofa tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It isstirred for 1 hour at 70° C, for 1.5 hours at −10° C., for 1 hour at 0°C. and for 2 hours at room temperature. Another spatula-tip full oftetrabutylammonium fluoride is added, and after stirring is continuedfor 20 minutes, it is added to water. It is extracted with ethylacetate, washed with water, dried with sodium sulfate and concentratedby evaporation in a vacuum. 297 mg of4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valericacid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 mlof ether at 0° C. with 29 mg of lithium aluminum hydride, and stirredfor 1 hour at 0° C. and for another 10 hours at room temperature. Thebatch is added to dilute hydrochloric acid, extracted with ethylacetate, washed with water, dried with sodium sulfate and concentratedby evaporation in a vacuum. 164 mg of4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-olis obtained as a yellow oil.

¹H-NMR (CDCl₃), δ (ppm)=1.40 (s, 3H), 1.48 (s, 3H), 2.20-2.28 (m, 2H),2.9 (s, 1H), 3.42 (d, 1H), 3.56 (d, 1H), 6.02 (d, 2H), 6.71 (d, 1H),6.94 (d, 1H).

MS (ei) m/e: M⁺=384 (⁷⁹Br)/386 (⁸¹Br).

Diol-Example b4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol

2-(4-Chlorophenyl)-2-methylpropanal:

10 g of 4-chlorobenzyl cyanide and 14.3 ml of methyl iodide in 140 ml ofDMF are mixed at 0° C. in portions with sodium hydride (60% in oil). Itis stirred overnight and then mixed with water and ethyl acetate. Thephases are separated, and the aqueous phase is extracted with ethylacetate.

It is extracted thoroughly with water, washed with brine, dried withsodium sulfate and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (hexane/ethyl acetate 95:5), 11.73 g of2-(4-chlorophenyl)-2-methylpropionitrile is obtained as a colorless oil.The latter is slowly mixed in toluene at −78° C. with 55.4 ml ofdiisobutylaluminium hydride solution (20% in toluene), and after 4 hoursat −78° C., 50 ml of ethyl acetate was added in drops. It is stirredovernight while being heated to room temperature, and water is added.After filtering through diatomaceous earth, the phases are separated,and the aqueous phase is extracted with ethyl acetate. It is washed withwater and brine, dried with sodium sulfate and concentrated byevaporation in a vacuum. After chromatography on silica gel(hexane/ethyl acetate 95:5), 10.2 g of2-(4-chlorophenyl)-2-methylpropanal is obtained as a colorless oil.

¹H-NMR (CDCl₃), δ (ppm)=1.46 (s, 6H), 7.20 (d, 1H), 7.29-7.43 (m, 3H),9.48 (s, 1H).

4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid:

A solution of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid-ethylester in 50 ml of tetrahydrofuran is mixed while being cooled with icewithin 20 minutes with 30 ml of a 2 M solution of lithiumdiisopropylamide in tetrahydrofuran-heptane-toluene, and it is stirredfor 15 minutes at 0° C. Within 30 minutes, a solution of 10.2 g of2-(4-chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran is addedin drops thereto at 0° C. After 20 hours at room temperature, 2Nsulfuric acid is added, it is extracted with ethyl acetate, dried(Na₂SO₄) and concentrated by evaporation. The crude product issaponified with 200 ml of 2 M sodium hydroxide solution/400 ml ofethanol. 13.8 g of acid, which is refluxed for 3 hours with 300 ml of 2Nsulfuric acid and 100 ml of glacial acetic acid while being stirredvigorously, is obtained. After extraction with ethyl acetate and washingwith water, 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid isobtained as a red oil.

¹H-NMR (CDCl₃), δ (ppm)=1.47 (s, 6H), 3.28 (s, 2H), 7.28 (s, 4H), 7.73(bs, 1H).

4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentan-1-ol:

Analogously to the synthesis of4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol(Diol Example 1), 4.22 g of4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol isobtained as a colorless oil by esterification of 10.9 g of4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid in ethanol/sulfuric acid,reaction of the product with trifluoromethyl-trimethylsilane andtetrabutylammonium fluoride and reduction of the formed hydroxy esterwith lithium aluminum hydride.

¹H-NMR (CDCl₃), δ (ppm)=1.39 (s, 3H), 1.49 (s, 3H), 2.07 (d, 1H), 2.19(d, 1H), 2.83 (bs, 1H), 3.27 (d, 1H), 3.41 (d, 1H), 7.26-7.38 (m, 4H).

Diol-Examples c and d4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-oland4-(2-Chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifuoromethyl)pentan-1-ol

A solution of 3 g of 2-hydroxy-4-methylene-2-(trifluoromethyl)valericacid ethyl ester in 22 ml of 3-chloroanisole is mixed at roomtemperature in portions with aluminum dichloride. It is stirred for 48hours and then mixed with 2N hydrochloric acid and hexane and stirredfor 1 hour. It is washed with 2N hydrochloric acid and water, and excess3-chloroanisole is distilled off in a vacuum. The remaining residue ispurified by chromatography on silica gel (hexane/ethyl acetate100:0→90:10). 2.85 g of a mixture of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methy-2-(trifluoromethyl)valericacid ethyl ester and4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methy-2-(trifluoromethyl)valericacid ethyl ester is obtained as a yellow oil. This substance mixture ismixed in 90 ml of ether at 0° C. with 445 mg of lithium aluminumhydride, and it is stirred for 12 hours. The batch is added to saturatedsodium bicarbonate solution, filtered through diatomaceous earth, thephases are separated, and the aqueous phase is extracted with ethylacetate. It is washed with water and brine, dried with sodium sulfateand concentrated by evaporation in a vacuum. After chromatography onsilica gel (hexane/ethyl acetate 95:5), 1.87 mg of4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-olis obtained as a first fraction, and 160 mg of4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-olis obtained as a second fraction as colorless oils.

1^(st) Fraction: ¹H-NMR (CDCl₃), δ (ppm)=1.41 (s, 3H), 1.51 (s, 3H),2.24 (d, 1H), 2.51 (d, 1H), 2.84 (bs, 1H), 3.36 (d, 1H), 3.48 (d, 1H),3.85 (s, 3H), 6.88 (d, 1H), 6.92 (dd, 1H), 7.24 (d, 1H).

2^(nd) Fraction: ¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 3H), 1.62 (s, 3H),2.18 (d, 1H), 2.76 (d, 1H), 2.93 (bs, 1H), 3.33 (d, 1H), 3.55 (d, 1H),3.80 (s, 3H), 6.78 (dd, 1H), 6.90 (d, 1H), 7.38 (d, 1H).

The following compounds were produced with the above-described processesof Diol-Example a to Diol-Example d:

TABLE I

Diol Synthesis Ex. Process R1/R2 Ra-Re (≠H) MS e b —CH₂—CH₂— Ra = ClM⁺ + 1 = 295 (³⁵Cl), 297 (³⁷Cl); (esi) f a CH₃, CH₃ Ra-Rb = —O-CH₂—O— M⁺= 306 (ei) g b CH₃, CH₃ Ra = Cl M⁺ = 296 (³⁵Cl), 298 (³⁷Cl); (ei) h bCH₃, CH₃ Rb = Cl M⁺ =296 (³⁵Cl), 298 (³⁷Cl); (ei) i a CH₃, CH₃ Ra-Rb =—O—CH₂—O—, M⁺ = 340 (³⁵Cl), 342 Rc = Cl (³⁷Cl); (ei) j b CH₃, CH₃ Ra =Rc = Cl M⁺ = 330 (2 × ³⁵Cl), 332 (³⁷Cl + ³⁵Cl), 334 (2 × ³⁷Cl); (ei) k bCH₃, CH₃ Ra = CF₃, Rd = F M⁺ = 348 (ei) l a CH₃, CH₃ Ra = OCH₃, M⁺ + 1 =329 (esi) Rb = Rd = F m b CH₃, CH₃ Ra = Rd = F M⁺ = 298 (ci) n b—(CH₃)₃— Ra = Cl, Rd = F M⁺ + NH₄ = 344 (ci) o b CH₃, CH₃ Ra = Cl, Rd =F 314, 316 (EI⁺) p b —(CH₂)₂— Ra = Cl, Rc = F 312, 314 (EI⁺) q b—(CH₂)₂— Ra = Cl, Rd = F 312, 314 (EI⁺) r b —(CH₂)₃— Ra = OCH₃, Rd = F322, 324 (EI⁺) s b CH₃, CH₃ Ra = Cl, Rc = F 378 (−Cl, EI⁺) t c CH₃, CH₃Ra = OCH₃, Rd = Br 370, 372 (EI⁺)

Example 76(±)-4-(7-Bromo-1,3-benzodioxol-4-yl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)pentan-2-ol

A solution of 160 mg of4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-oland 111 mg of 4-toluenesulfonic acid chloride in 1.5 ml of pyridine isstirred for 70 hours at 0° C. It is concentrated by evaporation in avacuum, taken up in 2N hydrochloric acid, and extracted with ethylacetate. It is washed with 2N hydrochloric acid and water, dried withsodium sulfate and concentrated by evaporation in a vacuum. 188 mg of4-toluenesulfonicacid-[4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)]pentylesteris obtained as a yellow oil. The latter is added to a solution, which isprepared from 94 mg of N-acetyl-5-amino-2-methylquinoline and sodiumhydride (60% in oil) in 1.5 ml DMF at 0° C., and it is stirred for 1.5hours. It is heated to 50° C. for 1 hour. It is stirred for another 70hours at room temperature and added to saturated sodium bicarbonatesolution. It is extracted with ethyl acetate, washed with water andbrine, dried with sodium sulfate and concentrated by evaporation in avacuum. After chromatography on silica gel (hexane/ethyl acetate100:0→85:15), 74 mg ofN-acetyl-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-olis obtained as a yellow oil. The latter is heated with 4 ml of ethanoland 1.2 ml of 1N sodium hydroxide solution for 8 hours to 100° C. It isconcentrated by evaporation in a vacuum and extracted with ethylacetate. It is washed with water and brine, dried with sodium sulfateand concentrated by evaporation in a vacuum. After chromatography onsilica gel (hexane/ethyl acetate 100:0→85:15), 51 mg of the titlecompound is obtained as a yellow foam.

¹H-NMR (CDCl₃), δ (ppm)=1.46 (s, 3H), 1.58 (s, 3H), 2.29 (d 1H), 2.50(d, 1H), 2.74 (s, 3H), 3.13 (bs, 1H), 3.18 (dd, 1H), 3.35 (dd, 1H), 4.30(bs, 1H), 5.98 (s, 2H), 6.11 (d, 1H), 6.80 (d, 1H), 7.00 (d, 1H), 7.21(d, 1H), 7.49 (d, 1H), 7.52 (d, 1H), 7.95 (d, 1H).

Examples 77, 78(−)-4-(7-Bromo-1,3-benzodioxol-4-yl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol(+)-4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol

Separation of(±)-4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol:

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol/triethylamine (98:2:0.1, vvv).

(−)-Enantiomer: MS (ei): M⁺=524 (⁷⁹Br) 526 (⁸¹Br), [ ]_(D)−50.4° (c=0.5,CHCl₃) and

(+)-Enantiomer: MS (ei): M⁺=524 (⁷⁹Br) 526 (⁸¹Br) are thus obtained.

Example 79(±)-4-(4-Chlorophenyl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol

0.674 ml of oxalyl chloride in 16.8 ml of dichloromethane is mixed at−78° C. with 1.15 ml of DMSO in 3.4 ml of dichloromethane. After 5minutes, 2 g of4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol in6.8 ml of dichloromethane is added in drops at −78° C. After 15 minutes,it is mixed with 4.7 ml of triethylamine and slowly heated to roomtemperature. It is washed with water and brine, dried with sodiumsulfate and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (hexane/ethyl acetate 98:2), 1.07 g of4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal isobtained as a colorless oil. 300 mg thereof was heated with 194 mg of5-amino-2-methylquinoline in 9 ml of glacial acetic acid for 4.5 hoursto 130° C. After toluene is added, it is concentrated by evaporation ina vacuum. The residue is taken up in methanol and mixed at 0° C. with153 mg of sodium borohydride. It is allowed to stir for 5 hours at roomtemperature, and water is added. The batch is concentrated byevaporation in a vacuum, extracted with ethyl acetate, washed with waterand brine, dried with sodium sulfate and concentrated by evaporation ina vacuum. After chromatography on silica gel (hexane/ethyl acetate100:0→85:15), 163 mg of the title compound is obtained as a yellowsolid.

Flash point: 137-139° C.

Examples 80, 81(−)-4-(4-Chlorophenyl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol(+)-4-(4-Chlorophenyl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol

Separation of(±)-4-(4-Chlorophenyl)-4-methyl-1-[(2-methylquinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol:

The enantiomer mixture is separated by chromatography on chiral carriermaterial (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (97:3,vvv).

(−)-Enantiomer: MS (esi): M⁺+1=437 (³⁵Cl) 439 (³⁷Cl), [α]_(D)=47.0°(c=0.75, CHCl₃) and

(+)-Enantiomer: MS (esi): M⁺+1=437 (³⁵Cl) 439 (³⁷Cl) are thus obtained.

Example 824-(1,3-Benzodioxol-4-yl)-4-methyl-1-[(quinolin-5-yl)amino]-2-(trifluoromethyl)pentan-2-ol

A solution that consists of 2.44 g of4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentan-1-oland 1.72 g of 4-toluenesulfonic acid chloride in 18 ml of pyridine isstirred for 70 hours at 9° C. It is concentrated by evaporation in avacuum, taken up in 2N hydrochloric acid and extracted with ethylacetate. It is washed with 2N hydrochloric acid and water, dried withsodium sulfate and concentrated by evaporation in a vacuum. Afterchromatography on silica gel (hexane/ethyl acetate 100:0→90:10), 3.97 gof 4-toluenesulfonicacid-[4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)]-pentylester is obtained as a colorless oil. 1.35 g thereof in 40 ml of THF ismixed with 118 mg of sodium hydride (60% in oil) and heated for 4 hoursto 60° C. Water is added, and it is extracted with ethyl acetate. It iswashed with water and brine, dried with sodium sulfate and concentratedby evaporation in a vacuum. After chromatography on silica gel(hexane/ethyl acetate 98:2), 630 mg of2-[2-(1,3-benzodioxol-4-yl)-2-(methylpropyl)]-2-(trifluoromethyl)oxiraneis obtained as a yellow oil. 230 mg thereof with 230 mg of5-aminoquinoline in 5 ml of DMSO is heated for 5 hours to 120° C. Wateris added, and it is extracted with ethyl acetate. It is washed withwater and brine, dried with sodium sulfate and concentrated byevaporation in a vacuum. After chromatography on silica gel(dichloromethane/acetone 99:1), 27 mg of the title compound is obtained.

MS (esi): M⁺+1=433.

According to the above-described process, the following compounds ofTable II were obtained:

TABLE II

Synthesis q1-q6 Ex. Process R1/R2 Ra-Re (≠H)¹⁾ (≠H)²⁾ Analysis³⁾Isomerism 83 Example CH₃/CH₃ Ra-Rb = —O—CH₂—O— q1 = CH₃ MS: M⁺ =Racemate 76 477 (ei) 84 Examples CH₃/CH₃ Ra-Rb = —O—CH₂—O— q1 = CH₃ MS:M⁺ = −51.2 (c = 1, 77, 78 477 (ei) CHCl₃) 85 Examples CH₃/CH₃ Ra-Rb =—O—CH₂—O— q1 = CH₃ MS: M⁺ = +54.7 77, 78 477 (ei) (c = 0.5, CHCl₃) 86Example CH₃/CH₃ Rb = Cl MS: M⁺ = Racemate 79 422/424 (ei) 87 ExamplesCH₃/CH₃ Rb = Cl MS: M⁺ = −28.1 (c = 80, 81 422/424 (ei) 0.35, MeOH/CHCl₃) 88 Examples CH₃/CH₃ Rb = Cl MS: M⁺ = +26.7 80, 81 422/424 (ei) (c =0.5, CHCl₃) 89 Example CH₃/CH₃ Rc = Cl MS: M⁺ = Racemate 79 423/425(esi) 90 Example CH₃/CH₃ Ra = Cl Flash point = Racemate 79 186-187° C.91 Examples CH₃/CH₃ Ra = Cl MS: M⁺ + 1 = −26.0 80, 81 423/425 (c = 0.5,(esi) CHCl₃) 92 Examples CH₃/CH₃ Ra = Cl MS: M⁺ = +17.3 80, 81 422/424(ei) (c = 1.1, CHCl₃) 93 Example CH₃/CH₃ Ra = Cl q1 = CH₃ MS: M⁺ =Racemate 79 436/438 (ei) 94 Examples CH₃/CH₃ Ra = Cl q1 = CH₃ MS: M⁺ =−15.5 80, 81 436/438 (ei) (c = 0.5, CHCl₃) 95 Examples CH₃/CH₃ Ra = Clq1 = CH₃ MS: M⁺ = +18.7 80, 81 436/438 (ei) (c = 0.6, CHCl₃) 96 ExampleCH₃/CH₃ Ra-Rb = —O—CH₂—O—, q1 = CH₃ MS: M⁺ = Racemate 76 Rc = Cl 480/482(ei) 97 Examples CH₃/CH₃ Ra-Rb = —O—CH₂—O—, q1 = CH₃ MS: M⁺ = −29.0 77,78 Rc = Cl 480/482 (c = 0.45, (ei) CHCl₃) 98 Examples CH₃/CH₃ Ra-Rb =—O—CH₂—O—, q1 = CH₃ MS: M⁺ = (+)− 77, 78 Rc = Cl 480/482 Enantiomer (ei)99 Example CH₃/CH₃ Rb = Cl q1 = CH₃ MS: M⁺ = Racemate 79 436/438 (ei)100 Examples CH₃/CH₃ Rb = Cl q1 = CH₃ MS: M⁺ = −34.6 80, 81 436/438 (ei)(c = 1.0, CHCl₃) 101 Examples CH₃/CH₃ Rb = Cl q1 = CH₃ MS: M⁺ = (+)− 80,81 436/438 (ei) Enantiomer 102 Example CH₃/CH₃ Ra = Rc = Cl q1 = CH₃ MS:M⁺ = Racemate 79 470, 472, 474 (ei) 103 Examples CH₃/CH₃ Ra = Rc = Cl q1= CH₃ MS: M⁺ = (−)− 80, 81 470, 472, Enantiomer 474 (ei) 104 ExamplesCH₃/CH₃ Ra = Rc = Cl q1 = CH₃ MS: M⁺ = +15.7 80, 81 470, 472, (c = 0.5,474 (ei) CHCl₃) 105 Example CH₃/CH₃ Ra = CF₃, Rd = F q1 = CH₃ MS: M⁺ =Racemate 79 488 (ei) 106 Examples CH₃/CH₃ Ra = CF₃, Rd = F q1 = CH₃ MS:M⁺ = −20.5 80, 81 488 (ei) (c = 1.0, CHCl₃) 107 Examples CH₃/CH₃ Ra =CF₃, Rd = F q1 = CH₃ MS: M⁺ = (+)− 80, 81 488 (ei) Enantiomer 108Example —CH₂—CH₂— Ra = Cl q1 = CH₃ MS: M⁺ + 1 = Racemate 79 435, 437(ci) 109 Examples —CH₂—CH₂— Ra = Cl q1 = CH₃ MS: M⁺ = −6.4 (c = 0.5, 80,81 434, 436 (ei) CHCl₃) 110 Examples —CH₂—CH₂— Ra = Cl q1 = CH₃ MS: M⁺ =+5.0 80, 81 434, 436 (ei) (c = 0.5, CHCl₃) 111 Example CH₃/CH₃ Ra =OCH₃, Rc = Cl q1 = CH₃ MS: M⁺ = Racemate 76 466, 468 (ei) 112 ExamplesCH₃/CH₃ Ra = OCH₃, Rc = Cl q1 = CH₃ MS: M⁺ = (−)− 77, 78 466, 468 (ei)Enantiomer 113 Examples CH₃/CH₃ Ra = OCH₃, Rc = Cl q1 = CH₃ MS: M⁺ =+34.1 77, 78 466, 468 (ei) (c = 1.0, CHCl₃) 114 Example CH₃/CH₃ Ra-Rb =—O—CH₂—O— q1 = Cl MS: M⁺ + 1 = Racemate 82 467, 469 (ci) 115 ExampleCH₃/CH₃ Ra = OCH₃, q1 = CH₃ MS: M⁺ + 1 = Racemate 76 Rb = Rd = F 469(esi) 116 Examples CH₃/CH₃ Ra = OCH₃, q1 = CH₃ MS: M⁺ = −11.0 77, 78 Rb= Rd = F 468 (ei) (c = 0.45, CHCl₃) 117 Examples CH₃/CH₃ Ra = OCH₃, q1 =CH₃ MS: M⁺ = (+)− 77, 78 Rb = Rd = F 468 (ei) Enantiomer 118 ExampleCH₃/CH₃ Ra = OH, q1 = CH₃ MS: M⁺ + 1 = −10.0 4 Rb = Rd = F 455 (esi) (c= 0.3, CHCl₃) 119 Example CH₃/CH₃ Ra = OH, q1 = CH₃ MS: M⁺ + 1 = (+)− 4Rb = Rd = F 455 (esi) Enantiomer 120 Example CH₃/CH₃ Ra = OH, Rc = Cl q1= CH₃ Flash point: (−)− 4 107-108° C. Enantiomer 121 Example CH₃/CH₃ Ra= OH, Rc = Cl q1 = CH₃ Flash point: (+)− 4 106-107° C. Enantiomer 122Example CH₃/CH₃ Ra = OCH₃, Rd = F q1 = CH₃, MS: M⁺ + 1 = Racemate 71 q6= F 469 (esi) 123 Example CH₃/CH₃ Ra = OH, Rd = F q1 = CH₃, MS: M⁺ + 1 =Racemate 4 q6 = F 455 (esi) 124 Example CH₃/CH₃ Ra = OCH₃, Rd = F q1 =CH₃, MS: M⁺ + 1 = Racemate 79 q4 = F 469 (esi) 125 Example CH₃/CH₃ Ra =OH, Rd = F q1 = CH₃, MS: M⁺ + 1 = Racemate 4 q4 = F 455 (esi) 126Example CH₃/CH₃ Ra-Rb = —O—CH₂—O— q1 = CH₃, MS: M⁺ + 1 = Racemate 79 q6= F 463 (esi) 127 Example CH₃/CH₃ Rb = Cl q1 = OH* MS: M⁺ + 1 = Racemate79 439, 441 (esi) 128 Example —CH₂—CH₂— Ra = Cl q1 = OH* MS: M⁺ + 1 =Racemate 79 435, 437 (ci) 129 Example CH₃/CH₃ Ra-Rb = —O—CH₂—O— q1 = OH*MS: M⁺ = Racemate 79 448 (ei) 130 Example CH₃/CH₃ Ra = OCH₃, Rc = Cl q1= OH* MS: M⁺ + 1 = Racemate 79 469, 471 (esi) 131 Example —CH₂—CH₂— Ra =Rd = F q1 = CH₃ MS: M⁺ + 1 = Racemate 76 437 (esi) 132 Example CH₃/CH₃Ra = Rd = F q1 = CH₃ MS: M⁺ + 1 = Racemate 79 438 (esi) 133 ExamplesCH₃/CH₃ Ra = Rd = F q1 = CH₃ (−)− 77, 78 Enantiomer 134 Examples CH₃/CH₃Ra = Rd = F q1 = CH₃ +27.1 77, 78 (c = 0.33, CHCl₃) 135 Example —(CH₂)₃—Ra = Rd = F q1 = CH₃ MS: M⁺ + 1 = 79 451 (ci) 136 Example —(CH₂)₃— Ra =Cl, Rd = F q1 = CH₃ MS: M⁺ + 1 = Racemate 79 467 (esi) 137 Examples—(CH₂)₃— Ra = Cl, Rd = F q1 = CH₃ (+)− 77, 78 Enantiomer 138 Examples—(CH₂)₃— Ra = Cl, Rd = F q1 = CH₃ −29.2 77, 78 (c = 0.61, CHCl₃) 139Examples CH₃/CH₃ Ra = OCH₃, Rc = Br Flash point: −32.7° 77,78 131-134°C., c = 0.5, THF MS: 496, 498 (EI⁺) 140 Examples CH₃/CH₃ Ra = OCH₃, Rc =Br Flash point: +36.7° 77, 78 132-135° C., c = 0.5, THF MS: 496, 498(EI⁺) 141 Example CH₃/CH₃ Ra = OH, Rc = Br Flash point: Racemate 4 105°C., MS: 482, 484 (EI+) 142 Examples CH₃/CH₃ Ra = OH, Rc = Br MS: 482,(−) 77, 78 484 (EI+) Enantiomer 143 Examples CH₃/CH₃ Ra = OH, Rc = BrMS: 482, +34.5° 77, 78 484 (EI+) c = 0.5, THF 144 Example CH₃/CH₃ Ra =OCH₃, Rc = Br q1 = CH₃ Flash point: Racemate 76 146-147° C. MS: 510, 512(EI⁺) 145 Examples CH₃/CH₃ Ra = OCH₃, Rc = Br q1 = CH₃ MS: 510, 512 (−)77, 78 (EI⁺) Enantiomer 146 Examples CH₃/CH₃ Ra = OCH₃, Rc = Br q1 = CH₃MS: 510, 512 +38.5° 77, 78 (EI⁺) c = 0.5, THF 147 Example CH₃/CH₃ Ra =OH, Rc = Br q1 = CH₃ MS: 496, Racemate 4 498 (EI³⁰ ) 148 ExamplesCH₃/CH₃ Ra = OH, Rc = Br q1 = CH₃ MS: 496, (−) 77, 78 498 (EI⁺)Enantiomer 149 Examples CH₃/CH₃ Ra = OH, Rc = Br q1 = CH₃ MS: 496,+41.2° 77,78 498 (EI⁺) c = 0.5, THF 150 Example CH₃/CH₃ Ra = OCH₃, Rd =Br Flash point: Racemate 76 138° C., MS: 496, 498 (EI⁺) 151 ExampleCH₃/CH₃ Ra = OH, Rd = Br MS: 482, Racemate 4 484 152 Examples CH₃/CH₃ Ra= OH, Rd = Br Flash point: (+) 77, 78 124-126° C., Enantiomer MS: 482,484 153 Examples CH₃/CH₃ Ra = OH, Rd = Br Flash point: −45.0° 77, 78124-126° C., c = 0.5, THF MS: 482, 484 154 Example CH₃/CH₃ Ra = OCH₃, Rd= Br q1 = CH₃ Flash point: Racemate 76 155° C., MS: 510, 512 (EI⁺) 155Examples CH₃/CH₃ Ra = OH, Rd = Br q1 = CH₃ MS: 496, (+) 77, 78 498 (EI⁺)Enantiomer 156 Examples CH₃/CH₃ Ra = OH, Rd = Br q1 = CH₃ MS: 496,−42.0° 77, 78 498 (EI⁺) c = 0.5, THF 157 Example CH₃/CH₃ Ra = Cl, Rd = FFlash point: Racemate 76 180-182° C., MS: 440, 442 (EI⁺) 158 ExamplesCH₃/CH₃ Ra = Cl, Rd = F Flash point: (+) 77, 78 141-142° C., EnantiomerMS: 440, 442 (EI⁺) 159 Examples CH₃/CH₃ Ra = Cl, Rd = F Flash point: (−)77, 78 142° C., MS: Enantiomer 440, 442 (EI⁺) 160 Example CH₃/CH₃ Ra =Cl, Rd = F q1 = CH₃ Flash point: Racemate 76 132-133° C., MS: 454, 456(EI⁺) 161 Examples CH₃/CH₃ Ra = Cl, Rd = F q1 = CH₃ Flash point: (+) 77,78 178° C., MS: Enantiomer 454, 456 (EI⁺) 162 Examples CH₃/CH₃ Ra = Cl,Rd = F q1 = CH₃ Flash point: −3.4° 77, 78 177° C., MS: c = 0.5, THF 454,456 (EI⁺) 163 Example —CH₂—CH₂— Ra = Cl, Rd = F Flash point: Racemate 76171° C., MS: 438, 440 (EI⁺) 164 Example —CH₂—CH₂— Ra = Cl, Rd = F q1 =CH₃ Flash point: Racemate 76 171° C., MS: 452, 454 (EI⁺) 165 ExampleCH₃/CH₃ Ra = Cl, Rc = F Flash point: Racemate 76 164-166° C., MS: 440(EI⁺) 166 Example CH₃/CH₃ Ra = Cl, Rc = F q1 = CH₃ Flash point: Racemate76 128-130° C., MS: 454, 456 (EI⁺) 167 Examples CH₃/CH₃ Ra = Cl, Rc = Fq1 = CH₃ Flash point: −1.5° 77, 78 128° C., MS: c = 0.5, THF 454, 456(EI⁺) 168 Examples CH₃/CH₃ Ra = Cl, Rc = F q1 = CH₃ Flash point: (+) 77,78 128° C., MS: Enantiomer 454, 456 (EI⁺) 169 Example —CH₂—CH₂— Ra = Cl,Rc = F Flash point: Racemate 76 172-173° C., MS: 452, 454 (EI⁺) 170Example —(CH₂)₃— Ra = OCH₃, Rd = F Flash point: Racemate 76 130° C., MS:448, 449 (EI⁺) 171 Examples —(CH₂)₃— Ra = OCH₃, Rd = F Flash point:−18.0° 77, 78 132-134° C., c = 0.5, THF MS: 448, 449 (EI⁺) 172 Examples—(CH₂)₃— Ra = OCH₃, Rd = F Flash point: (+) 77, 78 133-134° C.,Enantiomer MS: 448, 449 (EI⁺) 173 Example —(CH₂)₃— Ra = OH, Rd = F MS:434, Racemate 4 435 (EI³⁰ ) 174 Examples —(CH₂)₃— Ra = OH, Rd = F MS:434 −18.1° 77, 78 (EI⁺) c = 0.5, THF 175 Examples —(CH₂)₃— Ra = OH, Rd =F MS: 434 (+) 77, 78 (EI⁺) Enantiomer 176 Example —(CH₂)₃— Ra = OCH₃, Rd= F Flash point: Racemate 76 188° C., MS: 462, 463 (EI⁺) 177 Examples—(CH₂)₃— Ra = OCH₃, Rd = F Flash point: −13.2° 77, 78 188° C., c = 0.4,MS: 462, 463 CHCl₃ (EI⁺) 178 Examples —(CH₂)₃— Ra = OCH₃, Rd = F Flashpoint: (+) 77, 78 188° C., Enantiomer MS: 462, 463 (EI⁺) 179 Example—(CH₂)₃— Ra = OH, Rd = F q1 = CH₃ MS: 448, Racemate 4 449 180 Examples—(CH₂)₃— Ra = OH, Rd = F q1 = CH₃ MS: 448, −12.0° 77, 78 449 c = 0.4,CHCl₃ 181 Examples —(CH₂)₃— Ra = OH, Rd = F q1 = CH₃ MS: 448, (+) 77, 78449 Enantiomer 182 Example CH₃/CH₃ q6 = Br Flash point: Racemate 82 176°C., MS: 466, 466 (EI⁺) 183 Example CH₃/CH₃ Ra = OCH₃, Rd = F q6 = BrFlash point: Racemate 79 200° C., MS: 514, 516 (EI⁺) 184 Example CH₃/CH₃Ra = OH, Rd = F q6 = Br MS: 500, 502 Racemate 4 (EI⁺) 185 ExampleCH₃/CH₃ Ra = OCH₃, Rd = F q6 = Cl Flash point: Racemate 79 188-189° C.,MS: 470, 472 (EI⁺) 186 Example CH₃/CH₃ Ra = OH, Rd = F q6 = Cl Flashpoint: Racemate 4 184° C., MS: 456, 458 (EI⁺) 187 Example CH₃/CH₃ Ra =OCH₃, Rd = F q4 = Cl Flash point: Racemate 79 132° C., MS: 470, 472(EI⁺) 188 Example CH₃/CH₃ Ra = OH, Rd = F q4 = Cl MS: 456, 458 Racemate4 (EI⁺) ¹⁾Ra-Re (≠H) means that in the column, all radicals Ra-Re areindicated that do not mean hydrogen; any radicals Ra-Re that are notindicated = hydrogen ²⁾q1-q6 (≠H) means that all radicals q1-q6 areindicated that do not mean hydrogen; any radicals q1-q6 that are notindicated = hydrogen. ³⁾Analysis: MS = Mass spectrometry, flash point =melting point (fixed point) *OH is to indicate that the compound can bepresent as a tautomeric equilibrium

Example 189

4-(5-Fluoro-2-methoxyphenyl)-1-(isoquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 20, 500 mg (1.6 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanaland 500 mg (1.9 mmol) of 5-aminoisoquinoline in 16 ml of acetic acid arereacted to form4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(isoquinolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-oland subsequently reduced with 509 mg (2.4 mmol) of sodium triacetoxyborohydride. After chromatography on silica gel with hexane-ethylacetate (0-60%), 221 mg of product is obtained.

H-NMR (CDCl₃); δ=1.46 (s, 3H), 1.60 (s, 3H), 2.33 (d, 1H), 2.81 (d, 1H),3.12 (dd, 1H), 3.24 (br, 1H), 3.30 (dd, 1H), 3.84 (s, 3H), 4.32 (br,1H), 6.19 (dd, 1H), 6.78 (dd, 1H), 6.92 (td, 1H), 7.13 (dd, 1H), 7.38(m, 3H), 8.44 (d, 1H), 9.12 (s, 1H).

Example 190

4-(5-Fluoro-2-hydroxyphenyl)-1-(isoquinolin-5-yl)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to Example 2, 100 mg (0.15 mmol) of4-(5-fluoro-2-methoxyphenyl)-1-(isoquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-olis reacted with 4.6 ml of 1 M boron tribromide-CH₂Cl₂ solution. Afterchromatography on silica gel with hexane-ethyl acetate (0-80%), 13 mg ofthe product is obtained.

H-NMR (CD₃OD); δ=1.48 (s, 3H), 1.67 (s, 3H), 1.98 (d, 1H), 3.00 (d, 1H),3.25 (d, 1H), 3.43 (d, 1H), 6.22 (dd, 1H), 6.40 (dd, 1H), 6.53 (td, 1H),7.01 (dd, 1H), 7.34 (m, 2H), 7.71 (d, 1H), 8.37 (d, 1H), 9.06 (s, 1H).

Example 191

5-(5-Fluoro-2-methoxyphenyl)-5-methyl-2-(2-methylquinolin-5-ylamino)-3-(trifluoromethyl)hexan-3-ol

5-(5-Fluoro-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)hexane-2,3-diol

8 ml of 3 M methylmagnesium chloride-tetrahydrofuran solution is addedin drops to the solution of 3.6 mg (11.7 mmol) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanalin 150 ml of diethyl ether at +2° C. Stirring is continued for 1 hour at+2° C. and for 2 hours at room temperature. Then, it is hydrolyzed withsaturated ammonium chloride solution while being cooled with ice, theorganic phase is separated, dried on sodium sulfate and concentrated byevaporation. Column chromatography on silica gel with hexane-ethylacetate yields 2.23 g of the product.

5-(5-Fluoro-2-methoxyphenyl)-3-hydroxy-5-methyl-3-(trifluoromethyl)hexan-2-one

1.46 g (4.5 mmol) of5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)hexane-2,3-dioland 3.14 ml (22.5 mmol) of triethylamine in 16.3 ml of DMSO and 50 ml ofmethylene chloride are mixed in portions with 4.3 g (27 mmol) ofpyridine-sulfur trioxide complex at room temperature. After 20 hours atroom temperature, it is hydrolyzed with saturated ammonium chloridesolution while being cooled with ice and extracted with diethyl ether.The combined extracts are dried (sodium sulfate) and concentrated byevaporation. Column chromatography on silica gel with hexane-ethylacetate yields 1.04 g of the product.

5-(5-Fluoro-2-methoxyphenyl)-5-methyl-2-(2-methylquinolin-5-ylimino)-3-(trifluoromethyl)hexan-3-ol

645 mg (2 mmol) of5-(5-fluoro-2-methoxyphenyl)-3-hydroxy-5-methyl-3-(trifluoromethyl)hexan-2-one is refluxed in 4 ml of tetrahydrofuran under nitrogen with0.84 ml (4 mmol) of titanium tetraethylate and 348 mg (2.2 mmol) of5-amino-2-methylquinoline for 24 hours. After cooling to roomtemperature, the reaction mixture is stirred into 20 ml of saturatedNaCl solution, 50 ml of ethyl acetate is added, and it is stirred for 30minutes, suctioned off on Celite, and rewashed with ethyl acetate andwith tetrahydrofuran. The organic phase is separated, dried (sodiumsulfate) and concentrated by evaporation. Chromatography on silica gelwith hexane-ethyl acetate yields 578 mg of the product.

5-(5-Fluoro-2-methoxyphenyl)-5-methyl-2-(2-methylquinolin-5-ylamino)-3-(trifluoromethyl)hexan-3-ol

231 mg (0.5 mmol) of5-(5-fluoro-2-methoxyphenyl)-5-methyl-2-(2-methylquinolin-5-ylimino)-3-(trifluoromethyl)hexan-3-olis mixed in 10 ml of tetrahydrofuran and 4 ml of ethanol with 0.21 ml (1mmol) of titanium tetraethylate. Then, 875 mg (23.1 mmol) of sodiumborohydride is added in portions within 4 days at a reaction temperatureof 65° C. The reaction mixture is mixed with 20 ml of saturated NaClsolution after cooling to room temperature, stirred for 1 hour at roomtemperature, filtered on Celite, and rewashed with ethyl acetate andtetrahydrofuran. The organic phase is separated, washed with saturatedNaCl solution, dried and concentrated by evaporation. Columnchromatography on silica gel with hexane-ethyl acetate yields 68 mg ofthe product as a mixture of the two possible diastereomers.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding Germany Patent Application No. 102 15316.7, filed Apr. 2, 2002, and U.S. Provisional Application Ser. No.60/369,583, filed Apr. 4, 2002 are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound of formula I

wherein A stands for an aryl group, a benzyl group or a phenethyl group,optionally substituted by; one or more radicals of C₁-C₅-alkyl,C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-perfluoroalkyl, halogen, hydroxy,cyano, or nitro; or —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, or—(CH₂)_(n+2)—, wherein n=1 or 2, and wherein the two terminal atoms inthese groups are linked with directly adjacent ring-carbon atoms of thearyl, benzyl or phenethyl group to form a fused ring; or NR⁴R⁵, whereinR⁴ and R⁵, independently of one another, are hydrogen, C₁-C₅-alkyl or(CO)—C₁-C₅-alkyl, R¹ and R², independently of one another, are ahydrogen atom, a methyl or an ethyl group or together with the carbonatom of the chain from a C₃-C₆-cycloalkyl ring, R³ means a C₁-C₃-alkylgroup or a C₁-C₃-alkyl group optionally partially or completelyfluorinated, B means a methylene group that is optionally substituted bya methyl, an ethyl, or a carbonyl group, and Q means a quinolinyl groupor an isoquinolinyl group that is linked via any position and thatoptionally can be substituted by one or more radicals from the groupC₁-C₅-alkyl, wherein C₁-C₅-alkyl is optionally substituted by 1-3hydroxy groups and/or 1-3 COOR⁶ groups; C₁-C₅-alkoxy; C₁-C₅ alkylthio;C₁-C₅-perfluoroalkyl; halogen; hydroxy; a carbonyl-oxygen atom; cyano;nitro; or NR⁴R⁵, wherein R⁴ and R⁵, independently of one another, arehydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl; COOR⁶, wherein R⁶ meanshydrogen or a C₁-C₅-alkyl group; (CO)NR⁷R⁸, wherein R⁷ and R⁸,independently of one another, mean hydrogen or a C₁-C₅-alkyl group; or a(C₁-C₅-alkylen)-O—(CO)—(C₁-C₅)alkyl group; wherein, the C₁-C₅-alkylgroups in A, and R⁴-R⁸ are optionally substituted by 1-3 hydroxy groupsand/or 1-3 COOR⁶ groups; or a racemate, a separately presentstereoisomer, or a physiologically compatible salt thereof.
 2. Compoundsaccording to claim 1, wherein Q means a quinolinyl group or anisoquinolinyl group that is linked via any position and that optionallycan be substituted by one or more radicals from the group C₁-C₅-alkyl, acarbonyl-oxygen atom, COOR⁶, wherein R⁶ means hydrogen or a C₁-C₅-alkylgroup, (CO)NR⁷R⁸, wherein R⁷ and R⁸, independently of one another, meanhydrogen or a C₁-C₅-alkyl group, or a(C₁-C₅-alkylene)-O—(CO)—(C₁-C₅)alkyl group, wherein the C₁-C₅-alkyloptionally can be substituted by 1-3 hydroxy groups or 1-3 COOR⁶ groups.3. A compound of formula I

wherein A stands for an aryl group, a benzyl group or a phenethyl group,optionally substituted by; one or more radicals of C₁-C₅-alkyl,C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-perfluoroalkyl, halogen, hydroxy,cyano, or nitro; or —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, or—(CH₂)_(n+2)—, wherein n=1 or 2, and wherein the two terminal atoms inthese groups are linked with directly adjacent ring-carbon atoms of thearyl, benzyl or phenethyl group to form a fused ring; or NR⁴R⁵, whereinR⁴ and R⁵, independently of one another, are hydrogen, C₁-C₅-alkyl or(CO)—C₁-C₅-alkyl, R¹ and R², independently of one another, mean ahydrogen atom, a methyl or an ethyl group or together with the carbonatom of the chain form a C₃-C₆-cycloalkyl ring, R³ means a C₁-C₃-alkylgroup or a C₁-C₃-alkyl group optionally partially or completelyfluorinated, B means a methylene group that is optionally substituted bya methyl, an ethyl, or a carbonyl group, and Q means a quinolinyl groupor an isoquinolinyl group that is linked via any position and thatoptionally can be substituted by one or more radicals from the groupC₁-C₅-alkyl, ₁-C₅-alkoxy, C₁-C₅-perfluoroalkyl, halogen, hydroxy, cyano,nitro or NR⁴R⁵, wherein R⁴ and R⁵, independently of one another, can behydrogen, C₁-C₅-alkyl or (CO)—C₁-C₅-alkyl, or a racemate, a separatelypresent stereoisomer or a physiologically compatible salt.
 4. Acompounds according to claim 2, wherein B means a methylene group.
 5. Acompounds according to claim 2, wherein A is an aryl radical.
 6. Acompounds according to claim 5, wherein A is an aryl radical optionallysubstituted by one or more radicals from the group C₁-C₅-alkyl,C₁-C₅-alkoxy, C₁-C₅-perfluoroalkyl, halogen, hydroxy, or nitro, or—O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH—, or —(CH₂)_(n+2)—, whereinn=1 or 2, and their terminal atoms in these groups are linked withimmediately adjacent ring-carbon atoms.
 7. A compound according to claim2, wherein R¹ and R² together with the carbon atom of the chain mean aC₃-C₆-cycloalkyl ring.
 8. A compounds according to claim 2, wherein Qmeans an optionally substituted quinolinyl group that is linked via anyposition.
 9. A compound according to claim 5, wherein A is a phenylradical that is substituted by a hydroxy group, or a methoxy group, or ahalogen atom.
 10. A compounds according to claim 1, wherein the compoundis (+)-enantiomer.
 11. A compound according to claim 1, wherein thecompound is (−)-enantiomer.
 12. A pharmaceutical composition comprisinga compound according to claim 1, and a pharmaceutically acceptablevehicle.
 13. A method of treating an inflammatory disease, comprisingadministrating an effective amount of a compound according to claim 1 toa patient in need thereof.
 14. A compound according to claim 5, whereinA is phenyl or naphthyl.
 15. A compound according to claim 1, whereinthe C₁-C₅ alkyl groups in A, R⁴, R⁵, R⁶, R⁷, and R⁸ are, independently,a methyl, an ethyl, an n-propyl, an iso-propyl, an n-butyl, aniso-butyl, a tert-butyl, an n-pentyl, a 2,2-dimethylpropyl, a2-methylbutyl, or a 3-methylbutyl group, optionally substituted byhydroxy.
 16. A compound according to claim 1, wherein R¹ and R² aretogether a cyclopropyl ring.
 17. A compound according to claim 1,wherein B is a methylene group.
 18. A compound according to claim 1,wherein the C₁-C₅ alkoxy group in A and Q is a methoxy or an ethoxygroup.
 19. A compound according to claim 1, wherein the C₁-C₅-alkylthiogroup in A and Q is a methylthio or an ethylthio group.
 20. A compoundaccording to claim 1, wherein Q is a quinoline ring linked at the 4-, 5-or 8-position or an isoquinoline ring linked at the 1-position.